Therapeutic agent for osteoporosis and diazepine compound

ABSTRACT

A therapeutic agent for osteoporosis, comprising an azepine compound of the formula ##STR1## wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof as an active ingredient, a method for treating osteoporosis comprising administering said compound and a use of said compound for the production of a therapeutic agent for osteoporosis. The compounds of the formula (I) have superior bone resorption-inhibitory activity and act to reduce the increased amount of calcium in blood serum, which is caused by bone resorption. Accordingly, these compounds are usable as pharmaceutical agents to effectively inhibit bone resorption, to prevent decrease of bone mass and to prevent or suppress the increase of calcium amount in blood serum which is caused by the progress of bone resorption, with regard to Paget&#39;s disease, hypercalcemia, osteoporosis and so on in which the progress of bone resorption is considered to be deeply associated with the symptom, and to the symptoms of progressing bone resorption (development into osteoporosis) along with inflammatory joint diseases such as rheumatoid arthritis.

This application is a 371 of PCT/JP92/01325, filed Oct. 12, 1992 andpublished as WO93/07129 Apr. 15, 1993.

TECHNICAL FIELD

The present invention relates to a therapeutic agent for osteoporosiscontaining, as an active ingredient, a certain azepine compound havingsuperior bone resorption-inhibitory activity, a novel diazepinecompound, a method for treating osteoporosis and use of said compound.

BACKGROUND ART

The osteoporosis is a syndrome which develops a symptom wherein a bonemass per unit volume is unusually decreased without causing any changein the chemical composition (ratio between organic substance and mineralsubstance) of the ossein per se and physiologically characterized by adecrease in protein, calcium and phosphorus in the bone.

The decrease in bone mass as a symptom includes that caused byphysiological aging. Accordingly, the definition of the disease will bea remarkable decrease in bone mass which is greater than that caused bythe physiological aging and the manifestation of clinical symptoms suchas dorsolumbar pain, pathologic fracture, vertebral deformation and thelike.

The osteoporosis proceeds with aging and generally damages vertebra andcauses dorsolumbar pain and shortening of the height. In a very advancedcase, long bone is also damaged to sometimes cause fracture. The femoralfractures seen in old people are said to be mostly due to senileosteoporosis.

The causes of the osteoporosis are diverse and include abnormal internalsecretion inclusive of menopause, nutritional disorder and so on. Thevitamin D preparations, calcium preparations, calcitonin preparations,bisphosphonate preparations and so on conventionally used for treatingosteoporosis suffer from limitation on administration targets andunconclusive effects. As regards female hormone preparations, itsdependable effects are associated with severe side effects such asgenital cancer caused by a long-term use of the preparation.

Hence, the development of a therapeutic agent for osteoporosis, havingreliable effects and high safety is strongly demanded.

In recent years, thionaphthene-2-carboxylic acid derivative and3-phenyl-4H-1-benzopyran-4-one derivative (isoflavone derivative) havinga completely different chemical structure from the aforementionedpreparations have been reported to have bone resorption-inhibitoryactivity and to be useful as therapeutic agents for treatingosteoporosis (A. J. Johannesson et al, Endocrinology, 117, P. 1508,EP-A-135172, EP-A-136569, EP-A-146921, U.S. Pat. No. 4,644,012).

As the derivative having bone resorption-inhibitory activity,(cycloalkylamino)methylenebis(phosphonic acid) derivative (U.S. Pat. No.4,970,335), heterocyclic bisphosphonic acid derivative (U.S. Pat. No.4,990,503) and benzofuroquinoline derivative (EP-A-357172) have beenreported.

As the compounds having a diazepine skeleton, known are benzodiazepinecompounds, thienodiazepine compounds, benzotriazolodiazepine compounds,benzimidazolodiazepine compounds and thienotriazolodiazepine compounds,having antianxiety, sedative and muscle-relaxing actions. Specificexamples are bromazepam, clotiazepam, diazepam, flunitrazepam,flurazepam, lorazepam, medazepam, nitrazepam, oxazepam, azinazolam,alprazolam, brotizolam, estazolam, etizolam, midazolam and triazolam.

In addition, certain diazepine compounds such as devazepide and L-365260are known to have cholecystokinin (CCK) antagonistic action or gastrinantagonistic action (Japanese Patent Unexamined Publication Nos.63666/1986, 238069/1988 and 223290/1991 and W089/05812).

As the compounds having a platelet activating factor (PAF)-antagonisticaction and expected to be an antiasthma agent and a circulatory drug,known are thienotriazolodiazepine compounds such as4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,3-(4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl)propionicmorpholide,4-(3-(4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-2-yl)propionyl)morpholine,4-((6-(2-chlorophenyl)-8,9-dihydro-1-methyl-4H,7H-cyclopenta[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl)carbonyl)-morpholine,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-N,N-dipropyl-4H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine-8-carboxamide,6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine,and optical isomers thereof (Japanese Patent Unexamined Publication Nos.87623/1986, 87684/1986, 176591/1986, 181282/1987, 240686/1987,33382/1988, 35574/1988, 197484/1989, 98835/1990, 79185/1989, 79186/1989,85978/1989, 156982/1989, 256681/1990, 49787/1990, 191281/1990,243691/1990, 256682/1990, 275883/1990, 286684/1990, 289582/1990,145437/1991, 215489/1991, 264588/1991, 264589/1991, 66585/1992).

As stated above, the therapeutic agents for osteoporosis so far reporteddo not necessarily exhibit satisfactory effects and the development of acompound having superior action is awaited.

Accordingly, an object of the present invention is to provide a superiortherapeutic agent for osteoporosis. Another object of the presentinvention is to provide a novel compound to be used as an activeingredient of a therapeutic agent for osteoporosis.

A still another object of the present invention is to provide a methodfor treating osteoporosis and use for the treatment of osteoporosis.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies of boneresorption-inhibitory activity of certain azepine compounds in anattempt to develop a superior therapeutic agent for osteoporosis andfound that the azepine compounds show superior action, which resulted inthe completion of the invention.

Accordingly, the present invention relates to a therapeutic agent forosteoporosis, comprising an azepine compound of the formula ##STR2## ora pharmaceutically acceptable salt thereof as an active ingredient, amethod for treating osteoporosis comprising administering said compoundand a use of said compound for the production of a therapeutic agent forosteoporosis.

In the above formula, each symbol is as defined in the following.

Ar means aryl or heteroaryl;

X is an oxygen atom or a sulfur atom;

Y is hydrogen, alkyl, alkenyl, alkynyl, --(CH₂)aCOOR¹

wherein R¹ is hydrogen, alkyl, aryl or aralkyl and a is an integer of 1to 6, --(CH₂)a-cycloalkyl wherein a is an integer of 1 to 6,--(CH₂)aN(R²)(R³) wherein a is an integer of 1 to 6 and R² and R³ arethe same or different and each is hydrogen, alkyl or aralkyl, or form,together with the adjacent nitrogen atom, a heterocycle,--(CH₂)bCON(R⁴¹)(R⁴²) wherein b is 0 or an integer of 1 to 6, and R⁴¹and R⁴² are the same or different and each is hydrogen, alkyl, aryl oraralkyl, or form, together with the adjacent nitrogen atom, aheterocycle, --(CH₂)aCN wherein a is an integer of 1 to 6, or--(CH₂)aCR⁴ ₃ wherein a is an integer of 1 to 6 and R⁴ is halogen, or

X and Y combinedly form ═N--N═C(R⁶)--, ═N--C(R⁵)═C(R⁶)--,═C(R⁵)--N═C(R⁶)--, ═N--O--CO-- or ═N--N(R⁵)--CO-- wherein R⁵ and R⁶ areeach hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,aryloxyalkyl, --(CH₂)aCOOR⁷ wherein a is an integer of 1 to 6 and R⁷ ishydrogen, alkyl, alkenyl or aralkyl, or --(CH₂)aNHCOR⁴³ wherein a is aninteger of 1 to 6 and R⁴³ is alkyl or aralkyl;

W is --N(R³⁶)-- wherein R³⁶ is hydrogen or forms a bond with R³⁵, --O--or --S--;

R³⁵ is hydrogen or forms a bond with R³⁶ ;

R is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, aralkyl,heteroarylalkyl or a group of the formula selected from

    --(CH.sub.2)bN(R.sup.8)(R.sup.9)                           (1)

    --(CH.sub.2)bOR.sup.10                                     ( 2) ##STR3##

    --(CH.sub.2)bN(R.sup.10)CORa.sup.11                        ( 4)

    --(CH.sub.2)bN(R.sup.10)SO.sub.2 R.sup.44                  ( 5)

    --(CH.sub.2)bN(R.sup.10)COOR.sup.45                        ( 6) ##STR4##

    --(CH.sub.2)bOCOR.sup.46                                   ( 8)

    --(CH.sub.2)bCON(R.sup.47)(R.sup.48)                       (9)

    --(CH.sub.2)bOSO.sub.2 R.sup.44                            ( 10)

    --(CH.sub.2)bCOR.sup.49                                    ( 11)

    --(CH.sub.2)bS(O)nR.sup.11                                 ( 12)

    --CON(R.sup.10)OR.sup.8                                    ( 13) ##STR5##

    --CON(R.sup.10)N(R.sup.10)SO.sub.2 Ra.sup.11               ( 15) ##STR6##

    --CON(R.sup.10)N(R.sup.10)(R.sup.11)                       (18)

    --(CH.sub.2)bN(R.sup.10)COCON(R.sup.11)(R.sup.12)          (19)

and

    --(CH.sub.2)aCOOR.sup.1                                    ( 20)

wherein b is 0 or an integer of 1 to 6, Z is an oxygen atom or sulfuratom, R⁸ and R⁹ are the same or different and each is hydrogen, alkyl,aryl or aralkyl, R¹⁰ is hydrogen, alkyl or aralkyl, R¹¹ and R¹² are thesame or different and each is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, Ra¹¹ isalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl orheteroarylalkyl, R⁴⁴ is alkyl, aryl, aralkyl, cycloalkyl or heteroaryl,R⁴⁵ is alkyl, aryl or aralkyl, R⁴⁶ is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl orheteroarylalkyl, R⁴⁷ and R⁴⁸ are the same or different and each ishydrogen, alkyl, acyl, aryl or aralkyl, R⁴⁹ is alkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl, n is 0, 1 or 2, a is an integer of 1 to 6and R¹ is hydrogen, alkyl, aryl or aralkyl;

R' is hydrogen or --COOR⁸ wherein R⁸ is hydrogen, alkyl, aryl oraralkyl, or

R and R' combinedly form a spiro ring of the formula ##STR7## wherein b'is 0 or 1, R¹⁰ is hydrogen, alkyl or aralkyl and R¹² is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl orheteroarylalkyl;

ring Q is a ring selected from ##STR8## wherein R¹⁵ and R¹⁶ are the sameor different and each is hydrogen, halogen, alkyl optionally substitutedby halogen, alkoxy, nitro, amino, amino substituted by alkyl, cyclicamino, hydroxy, acyloxy, cyano, carbamoyl, carbamoyl substituted byalkyl, cyclic aminocarbonyl, carboxyl, alkoxycarbonyl oraralkyloxycarbonyl, aralkyl, aralkyl substituted by alkyl, alkoxy,nitro, amino, amino substituted by alkyl, cyclic amino, hydroxy,acyloxy, cyano, carbamoyl, carbamoyl substituted by alkyl, cyclicaminocarbonyl, carboxyl, alkoxycarbonyl or aralkyloxycarbonyl;

R¹⁷ and R¹⁸ are the same or different and each is hydrogen, halogen,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, nitro, amino, aminosubstituted by alkyl, cyclic amino, hydroxy, acyloxy, cyano, carbamoyl,carbamoyl substituted by alkyl, cyclic aminocarbonyl, carboxyl,alkoxycarbonyl, aralkyloxycarbonyl, cycloalkyl, alkylcarbonyl, a groupof the formula

    R.sup.19 --A--

wherein A is alkylene, alkenylene or alkynylene which may be substitutedby 1 to 3 hydroxys and R¹⁹ is alkoxy, nitro, amino, hydroxy, acyloxy,cyano, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, phenyl optionallysubstituted by 1 to 3 substituents (e.g. halogen, hydroxy, alkyl,alkoxy, aryl, aryloxy, aralkyl, aralkyloxy, alkenyl or alkynyl having 2to 18 carbon atoms, which may be substituted by 1 to 3 hydroxys,aralkenyl or aralkynyl having alkenyl moiety or alkynyl moiety having 2to 18 carbon atoms, which may be substituted by 1 to 3 hydroxys), agroup of the formula

    (R.sup.20)(R.sup.21)NCO-- or (R.sup.20)(R.sup.21)N--SO.sub.2 --

wherein R²⁰ and R²¹ are the same or different and each is hydrogen,aryl, aralkyl or straight- or branched chain alkyl, alkenyl or alkynylwhich may be substituted by halogen, hydroxy, nitro, amino orsubstituted amino, or R²⁰ and R²¹ may, together with the adjacentnitrogen atom, form a 3 to 7-membered ring which may be substituted bystraight- or branched chain alkyl and may have, in the ring, nitrogen,oxygen or sulfur atom as a hetero atom (the additional nitrogen atom maybe substituted by straight- or branched chain alkyl having 1 to 4 carbonatoms, aralkyl or diarylalkyl), a group of the formula

    (R.sup.22)(R.sup.23)N--

wherein R²² and R²³ are the same or different and each is hydrogen,straight- or branched chain alkyl, alkenyl or alkynyl, which may besubstituted by halogen, hydroxy, amino, alkylamino, dialkylamino, cyclicamino or C-bonded heterocyclic group (carbons may be interrupted bynitrogen, oxygen or sulfur atom), straight- or branched chainalkylcarbonyl which may be mono- or di-substituted by hydroxy, halogen,amino, alkylamino, dialkylamino, cyclic amino or straight- or branchedchain alkyl (this alkyl may be substituted by halogen or hydroxy),arylcarbonyl, arylsulfonyl, alkylsulfonyl, or R²² and R²³ may form,together with the adjacent nitrogen atom, a saturated or unsaturated 3to 7-membered ring which may be substituted by straight- or branchedchain alkyl and may have, in the ring, nitrogen, oxygen or sulfur atomas a hetero atom (each additional nitrogen atom may be substituted bystraight- or branched chain alkyl), a group of the formula ##STR9##wherein R²⁴ is aryl, aralkyl, arylcarbonyl, a group of the formula##STR10## wherein R²⁵ and R²⁶ are the same or different and each ishydrogen, halogen, haloalkyl, amino, nitro, cyano, hydroxy, alkyl oralkoxy and B is hydrogen, hydroxy or esterified hydroxy, or alkyl havinghydroxy and/or carbonyl and X¹ is CH or nitrogen atom, or a group of theformula ##STR11## wherein R²⁷ and R²⁸ are the same or different and eachis hydrogen, halogen, haloalkyl, amino, nitro, cyano, hydroxy, alkyl oralkoxy, a group of the formula

    R.sup.29 --(CH.sub.2)d--C.tbd.C--

wherein R²⁹ is aryl or optionally hydrogenated heteroaryl and d is 0, 1or 2, a group of the formula

    R.sup.29 --O--(CH.sub.2)e--C.tbd.C--

wherein R²⁹ is as defined above and e is 1 or 2, or a group of theformula ##STR12## wherein X⁰ is --OCO--, --CO-- or --N(R⁵¹)CO-- whereR⁵¹ is hydrogen or alkyl, m is 0 or 1, R⁵⁰ is alkyl, alkynyl,2-phenylethynyl, 2-thienylsulfonyl, --(CH₂)aCN where a is an integer of1 to 6, --(CH₂)b-R⁵² where b is 0 or an integer of 1 to 6 and R⁵² iscycloalkyl, morphlino, thienyl, alkoxy, aryl, imidazolyl ortetrahydropyranyl or --SO₂ N(R⁵³)(R⁵⁴) where R⁵³ and R⁵⁴ are the same ordifferent and each is hydrogen, alkyl, or R⁵³ and R⁵⁴, with the adjacentnitrogen atom, form a heterocycle, or

adjacent R¹⁷ and R¹⁸ may combinedly form a saturated or unsaturated 5, 6or 7-membered ring which is condensed to thiophene ring, said ring beingoptionally substituted by a substituent Ra³⁰ selected from hydrogen,halogen, alkyl, a group of the formula R¹⁹ --A-- wherein each symbol isas defined above and a group of the formula (R²⁰)(R²¹)NCO-- or(R²⁰)(R²¹)N--SO₂ -- wherein each symbol is as defined above, or R¹⁷ andR¹⁸ may combinedly form a 5, 6 or 7-membered hetero ring which may haveoxygen, sulfur or --N(Rb³⁰)-- as a hetero atom.

Examples of Rb³⁰ include hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,alkoxycarbonyl, alkanoyl, aroyl, cycloalkylcarbonyl,cycloalkoxycarbonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylaminocarbonyl, a group of the formula R¹⁹ --A-- wherein eachsymbol is as defined above, a group of the formula (R²⁰)(R²¹)NCO--wherein each symbol is as defined above, a group of the formula(R²⁰)(R²¹)N--SO₂ -- wherein each symbol is as defined above, a group ofthe formula Ra³¹ --SO₂ -- wherein Ra³¹ is alkyl, phenyl, phenylsubstituted by halogen, alkyl, alkoxy, carboxy, alkylsulfonyl,alkylthio, haloalkyl or optionally substituted phenoxy, heteroaryl ornaphthyl, a group of the formula ##STR13## wherein Y¹ is oxygen atom orsulfur atom and Rb³¹ is alkenyl, alkyl, cycloalkyl, aryl, aralkyl,heteroaryl, heteroarylalkyl, phenyl substituted by 1 to 3 substituentsselected from alkyl, alkoxy, aryloxy, alkylsulfonyl, halogen andhaloalkyl, quinolyl or sulfonyl substituted by phenyl, heteroaryl ornaphthyl, or a group of the formula ##STR14## wherein Y¹ is oxygen atomor sulfur atom and Rb³¹ is alkyl, phenyl substituted by phenyl, halogen,alkyl, alkoxy, haloalkyl or optionally substituted phenoxy, orheteroaryl.

In the above definitions, aryl, aryloxy, aryloxyalkyl, arylcarbonyl,arylsulfonyl, aralkyl, aralkyloxy, aralkyloxycarbonyl, aralkenyl,aralkynyl, diarylalkyl, heteroaryl and heteroarylalkyl may have, on thering, 1 to 3 substituents selected from halogen, alkyl, alkoxy,haloalkyl, hydroxy, nitro, amino, cyano and acyloxy. Cycloalkyl ofcycloalkyl, cyclo-alkylalkyl, cycloalkylcarbonyl,cycloalkylalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyland cycloalkylaminocarbonyl may have 1 to 3 substituents selected fromhalogen, alkyl, alkoxy, haloalkoxy and aryl.

Furthermore, the present invention provides a diazepine compound of theformula ##STR15## wherein R³² is optionally substituted phenyl oroptionally substituted phenylalkyl and other symbols are as definedabove, a pharmaceutically acceptable salt thereof, a diazepine compoundof the formula ##STR16## wherein a is an integer of 1 to 6, R³³ and R³⁴are the same or different and each is alkyl or aralkyl or R³³ and R³⁴may combinedly form a 5 to 7-membered ring which may have, in the ring,nitrogen, sulfur or oxygen atom, the ring Q¹ is ##STR17## wherein R¹⁷and R¹⁸ are as defined above, and other symbols are as defined above,and a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a benzotriazolodiazepinecompound of the formula ##STR18## wherein R¹⁵ ' is alkyl or aralkylhaving 8 to 15 carbon atoms, R¹⁶ ' is hydrogen and other symbols are asdefined above, a pharmaceutically acceptable salt thereof, abenzotriazolodiazepine compound of the formula ##STR19## wherein R" is agroup of the formula selected from

    --CON(R.sup.47)(R.sup.48)                                  (9')

    --CON(R.sup.10)OR.sup.8                                    ( 13) ##STR20##

    --CON(R.sup.10)N(R.sup.10)(R.sup.11)                       (18)

and

    --N(R.sup.10)CON(R.sup.10)Py                               (21)

wherein Py is optionally substituted pyridyl and other symbols are asdefined above, R' is hydrogen or R" and R' may combinedly form a spiroring of the formula ##STR21## wherein each symbol is as defined above,and other symbols are as defined above, and a pharmaceuticallyacceptable salt thereof.

The preferable modes of the present invention include the following.

(1) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein W is --(NR³⁶)-- whereR³⁶ forms a bond with R³⁵, or a pharmaceutically acceptable saltthereof, a method for treating osteoporosis by the administration ofsaid compound and a use of said compound for producing a therapeuticagent for osteoporosis.

(2) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein W is --(NR³⁶)-- whereR³⁶ forms a bond with R³⁵ and X and Y combinedly form ═N--N═C(R⁶)--where R⁶ is as defined above, or a pharmaceutically acceptable saltthereof, a method for treating osteoporosis by the administration ofsaid compound and a use of said compound for producing a therapeuticagent for osteoporosis.

(3) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein W is --(NR³⁶)-- whereR³⁶ forms a bond with R³⁵ and X and Y combinedly form ═N--N═C(R⁶ ')--where R⁶ 'is alkyl having 6 to 20 carbon atoms, or a pharmaceuticallyacceptable salt thereof, a method for treating osteoporosis by theadministration of said compound and a use of said compound for producinga therapeutic agent for osteoporosis.

(4) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein the ring Q is##STR22## wherein R¹⁷ and R¹⁸ are as defined above, or apharmaceutically acceptable salt thereof, a method for treatingosteoporosis by the administration of said compound and a use of saidcompound for producing a therapeutic agent for osteoporosis.

(5) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein W is --(NR³⁶)-- whereR³⁶ forms a bond with R³⁵, R is alkyl, aryl, heteroaryl, aralkyl,heteroarylalkyl or a group of the formula selected from

    --(CH.sub.2)bN(R.sup.8)(R.sup.9)                           (1)

    --(CH.sub.2)bOR.sup.10                                     ( 2) ##STR23##

    --(CH.sub.2)bN(R.sup.10)CORa.sup.11                        ( 4)

    --(CH.sub.2)bN(R.sup.10)SO.sub.2 R.sup.44                  ( 5)

    --(CH.sub.2)bN(R.sup.10)COOR.sup.45                        (6) ##STR24##

    --(CH.sub.2)bOCOR.sup.46                                   ( 8)

    --(CH.sub.2)bCON(R.sup.47)(R.sup.48)                       (9)

    --(CH.sub.2)bOSO.sub.2 R.sup.44                            ( 10)

    --(CH.sub.2)bCOR.sup.49                                    ( 11)

    --(CH.sub.2)bS(O)nR.sup.11                                 ( 12)

    --CON(R.sup.10)OR.sup.8                                    ( 13) ##STR25##

    --CON(R.sup.10)N(R.sup.10)SO.sub.2 Ra.sup.11               ( 15) ##STR26##

    --CON(R.sup.10)N(R.sup.10)(R.sup.11)                       (18)

    --(CH.sub.2)bN(R.sup.10)COCON(R.sup.11)(R.sup.12)          (19)

and

    --(CH.sub.2)aCOOR.sup.1                                    ( 20)

wherein each symbol is as defined above and the ring Q is a group of theformula ##STR27## wherein each symbol is as defined above, or apharmaceutically acceptable salt thereof, a method for treatingosteoporosis by the administration of said compound and a use of saidcompound for producing a therapeutic agent for osteoporosis.

(6) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein W is --(NR³⁶)--wherein R³⁶ forms a bond with R³⁵, R is alkyl, aryl, aralkyl or a groupof the formula selected from

    --(CH.sub.2)bN(R.sup.8 )(R.sup.9)                          (1) ##STR28##

    --(CH.sub.2)bN(R.sup.10)CORa.sup.11                        ( 4)

    --(CH.sub.2)bN(R.sup.10)SO.sub.2 R.sup.44                  ( 5)

    --(CH.sub.2)bN(R.sup.10)COOR.sup.45                        ( 6) ##STR29##

    --(CH.sub.2)bCON(R.sup.47)(R.sup.48)                       (9)

    --(CH.sub.2)bOSO.sub.2 R.sup.44                            ( 10)

    --(CH.sub.2)bCOR.sup.49                                    ( 11)

    and

    --(CH.sub.2)aCOOR.sup.1                                    ( 20)

wherein each symbol as defined above and the ring Q is a group of theformula ##STR30## wherein each symbol is as defined above, or apharmaceutically acceptable salt thereof, a method for treatingosteoporosis by the administration of said compound and a use of saidcompound for producing a therapeutic agent for osteoporosis.

(7) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) which is selected from:

9-tert-butyl-4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionicmorpholide,

4-(2-chlorophenyl)-6,9-dimethyl-2-(3-morpholinopropyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

4-(2-chlorophenyl)-6-isobutyl-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6-phenyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

6-benzyl-4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-indolecarboxamide,

N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-3-indoleacetamide,

6-benzoylamino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

4-(2-chlorophenyl)-2-ethyl-9-methyl-6-(3-(3-tolyl)ureido)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

8S-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

6-(2-chlorophenyl)-8,9-dihydro1,4-dimethyl-8-morpholinocarbonyl-4H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid,

N-(2-methoxyphenyl)-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide,

N-phenyl-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide,

N-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-p-toluenesulfonamide,

(4-(4-methoxyphenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-methylphenyl)carbamate,

4-(2-chlorophenyl)-2-ethyl-9-methyl-6-phenylacetylamino-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

N-(4-chlorophenyl)-N'-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)urea,

N-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methoxyphenyl)urea,

N-(4-(4-chlorophenyl)-2-hexyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea,

N-(4-(2-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea,

N-(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methoxyphenyl)urea,

N-(2-ethyl-9-methyl-4-(4-methylphenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea,

N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-phenylurea,

N-(2-ethyl-9-methyl-4-phenyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea,

N-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(2-methoxyphenyl)urea,

N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-phenylthiourea,

N-(2-butyl-4-(4-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea,

N-(4-(2-chlorophenyl)-2-ethyl-9-cyclohexyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(2-methylphenyl)urea,

4-(4-chlorophenyl)-2-ethyl-9-methyl-6-(3-phenylpropyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,

2-ethyl-4-phenyl-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine,

6-(2-chlorophenyl)-1-undecyl-7,8,9,10-hexahydro-4H,6H-triazolo[3,4-c][1]benzothieno[2,3-e][1,4oxazepine,

4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine,

4-(4-chlorophenyl)-2-ethyl-9-(3-(4-isobutylphenyl)propyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine,

2-ethyl-9-heptyl-4-(4-methoxyphenyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine,

2-ethyl-4-(4-methylphenyl)-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine,

2-ethyl-4-(4-hydroxyphenyl)-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine,and

2-ethyl-4-(4-(2-dimethylaminoethoxy)phenyl)-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine

or a pharmaceutically acceptable salt thereof, a method for treatingosteoporosis by the administration of said compound and a use of saidcompound for producing a therapeutic agent for osteoporosis.

(8) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein the ring Q is a groupof the formula ##STR31## wherein R¹⁵ and R¹⁶ are as defined above, or apharmaceutically acceptable salt thereof, a method for treatingosteoporosis by the administration of said compound and a use of saidcompound for producing a therapeutic agent for osteoporosis.

(9) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) wherein the ring Q is a groupof the formula ##STR32## wherein R¹⁵ and R¹⁶ are as defined above, N is--(NR³⁶)-- where R³⁶ is hydrogen or forms a bond with R³⁵ or --O--, R ishydrogen, heteroarylalkyl or a group of the formula selected from##STR33##

    --(CH.sub.2)bN(R.sup.10)SO.sub.2 R.sup.44                  ( 5)

    --(CH.sub.2)bN(R.sup.10)COOR.sup.45                        ( 6) ##STR34##

    --(CH.sub.2)bOCOR.sup.46                                   ( 8)

    --(CH.sub.2)bCON(R.sup.47)(R.sup.48)                       (9)

    --(CH.sub.2)bOSO.sub.2 R.sup.44                            ( 10)

    --CON(R.sup.10)OR.sup.8                                    ( 13) ##STR35##

    --CON(R.sup.10)N(R.sup.10)(R.sup.11)                       (18)

where in each symbol is as defined above, and R' is hydrogen or --COOR⁸wherein R⁸ is as defined above, or R and R' combinedly form a spiro ringof the formula ##STR36## wherein each symbol is as defined above, or apharmaceutically acceptable salt thereof, a method for treatingosteoporosis by the administration of said compound and a use of saidcompound for producing a therapeutic agent for osteoporosis.

(10) A therapeutic agent for osteoporosis containing, as an activeingredient, a compound of the formula (I) which is selected from

6-(4-chlorophenyl)-1-undecyl-4H,6H-[1,2,4]triazolo[4,3-a][1,4]benzoxazepine

8-decyl1,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

9-decyl1,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

6-(4-chlorophenyl)-1-undecyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

6-(4-chlorophenyl)-1-undecyl-4H,5H,6H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

6-(4-chlorophenyl)-1-(3-(isobutylphenyl)propyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

N-benzoyl-N'-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(2-pyridyl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(3-pyridyl)urea,

N-(8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(2-methoxyphenyl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(2-methoxyphenyl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(3-tolyl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-phenyl-oxalyldiamide,

N-(1-methyl-6-(2-thienyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(3-tolyl)urea,

6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-spiro-5'-(3'-(3-tolyl)-2',4'-dioxoimidazolidine),

N-(6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(3-tolyl)urea,

(1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl-p-toluenesulfonate,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl-N'-(2-methoxyphenyl)urea,

N-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl]-N'-(3-tolyl)urea,

N-(3-tolyl)-O-((1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl)carbamate,

N-(2-methoxyphenyl)-O-((1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl)carbamate,

(1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methylphenylacetate,

6-(4-chlorophenyl)-4-(3-indolylmethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-O-benzylcarbamate,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)benzylsulfonamide,

(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydrazide,

N'-p-tosyl-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydrazide,

O-benzyl-N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydroxamate,

N-benzyl-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-yl)carboxamide,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl-2-indolecarboxamide,

N-benzyl-N'-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(cyclohexyl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-2-indolecarboxamide,

8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

8-chloro-6-phenyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,and

8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine

or a pharmaceutically acceptable salt thereof, a method for treatingosteoporosis by the administration of said compound and a use of saidcompound for producing a therapeutic agent for osteoporosis.

(11) A benzotriazolodiazepine compound selected from

8-decyl1,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][14]benzodiazepine,

9-decyl1,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

N-benzoyl-N'-6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)urea,

N-(p-tosyl)-N'-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(2-pyridyl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(3-pyridyl)urea,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-phenyl-oxalyldiamide,

N-(1-methyl-6-(2-thienyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(3-tolyl)urea,

6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-spiro-5'-(3'-(3-tolyl)-2'-4'-dioxoimidazolidine),

N'-phenyl-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydrazide,

N'-benzoyl-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydrazide,

O-benzyl-N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydraxamate,

N-benzyl-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carboxamide,

6-(4-chlorophenyl)-1-undecyl-4H,5H,6H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,

(1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl-p-toluenesulfonate,

(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydrazide,

N'-p-tosyl-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydrazide,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)methyl-2-indolecarboxamide,

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-N'-(cyclohexyl)urea,and

N-(6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)-2-indolecarboxamide

or a pharmaceutically acceptable salt thereof.

As used herein, each substituent is defined as follows.

Aryl in Ar, R¹ , R⁵ and R⁶ is phenyl which may have, on the ring, 1 to 3substituents selected from halogen (chlorine, bromine, fluorine), alkyl(alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, isobutyl, pentyl, isopentyl and hexyl),alkoxy (alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy and hexyloxy), haloalkyl (thatwherein alkyl moiety is C1-C4 alkyl, such as chloromethyl, bromomethyl,fluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoropropyl andchlorobutyl), hydroxy, nitro, amino, cyano, acyloxy (e.g. that whereinacyl moiety is alkanoyl having 2 to 5 carbon atoms, such as acetyl,propionyl, butyryl and pivaloyl, or aroyl (e.g. benzoyl which may have,on the ring, 1 to 3 substituents selected from halogen (as definedabove), alkyl (as defined above), alkoxy (as defined above), haloalkyl(as defined above) and hydroxy, such as benzoyl, chlorobenzoyl,methylbenzoyl and methoxybenzoyl) and aralkyl (that wherein alkyl moietyhas 1 to 6 carbon atoms, which may have, on the ring, 1 to 3substituents selected from halogen (as defined above), alkyl (as definedabove), alkoxy (as defined above), and hydroxy, such as benzyl,2-phenylethyl and 3-phenylpropyl).

Heteroaryl of Ar is pyridyl or thienyl which may have, on the ring, 1 to3 substituents selected from halogen (chlorine, bromine, fluorine),alkyl (alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, isobutyl, pentyl, isopentyl and hexyl),alkoxy (alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy and hexyloxy), haloalkyl (thatwherein alkyl moiety is alkyl having 1 to 4 carbon atoms, such aschloromethyl, bromomethyl, fluoromethyl, trifluoromethyl,trifluoroethyl, pentafluoropropyl and chlorobutyl), hydroxy, nitro,amino, cyano, acyloxy (e.g. that wherein acyl moiety is alkanoyl having2 to 5 carbon atoms, such as acetyl, propionyl, butyryl and pivaloyl, oraroyl such as benzoyl which may have, on the ring, 1 to 3 substituentsselected from halogen (as defined above), alkyl (as defined above),alkoxy (as defined above), haloalkyl (as defined above) and hydroxy,such as benzoyl, chlorobenzoyl, methylbenzoyl and methoxybenzoyl).

Unless otherwise specified, as used in the present specification, alkylmeans straight or branched alkyl having 1 to 20 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,tert-pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, 2,2-diethyloctyl,1,1,3,3-tetramethylbutyl, nonyl, decyl, undecyl, dodecyl, tetradecyl,pentadecyl, octadecyl, heptadecyl and eicosyl. The preferable carbonnumber of the alkyl is 1 to 6.

Unless specifically indicated, alkenyl means that having 2 to 20 carbonatoms, such as vinyl, propenyl, 2-methyl-1-propenyl, 3-methyl-1-butenyl,2,3-dimethyl-1-butenyl, 3,4,5-trimethyl-1-butenyl, 3-butenyl, 3-hexenyl,5-dodecenyl, 6-ethyl -3-decenyl, 11,11-dimethyl-7-tetradecenyl,14-octadecenyl and 8-eicosenyl. The preferable carbon number of thealkenyl is 2 to 8.

Unless specifically indicated, alkynyl means that having 2 to 20 carbonatoms, such as 1-propynyl, 3-methyl-1-butynyl, 1,4-dimethyl-1-hexynyl,ethynyl, propargyl, 3-hexynyl, 3,4-diethyl-1-octynyl, 5-dodecynyl,6-ethyl-3-decynyl, 11,11-dimethyl-7-tetradecynyl, 14-octadecynyl and8-eicosynyl. The preferable carbon number of the alkynyl is 2 to 8.

Aralkyl is that where aryl moiety is phenyl and alkyl moiety is C1-C6alkyl and exemplified by benzyl, phenylethyl, phenylpropyl, phenylbutyland phenylhexyl, which may have, on the ring, 1 to 3 substituentsselected from halogen (chlorine, bromine, fluorine), alkyl (alkyl having1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, isobutyl, pentyl, isopentyl and hexyl), alkoxy (alkoxyhaving 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, tert-butoxy and hexyloxy), haloalkyl (that wherein alkyl moietyis alkyl having 1 to 4 carbon atoms, such as chloromethyl, bromomethyl,fluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoropropyl andchlorobutyl), hydroxy, nitro, amino, cyano, acyloxy (e.g. that whereinacyl moiety is alkanoyl having 2 to 5 carbon atoms such as acetyl,propionyl, butyryl and pivaloyl, or aroyl such as benzoyl which mayhave, on the ring, 1 to 3 substituents selected from halogen (as definedabove), alkyl (as defined above), alkoxy (as defined above), haloalkyl(as defined above) and hydroxy, such as benzoyl, chlorobenzoyl,methylbenzoyl and methoxybenzoyl).

Cycloalkyl has 3 to 10 carbon atoms and is exemplified by cyclopropyl,2,3-dimethylcyclopropyl, cyclobutyl, 3-methylcyclobutyl, cyclopentyl,3,4-dimethylcyclopentyl, cyclohexyl, 4-methylcyclohexyl, cycloheptyl,cyclooctyl, norbornyl, adamantyl, bicyclo[3.3.0]octan-1-yl andbicyclo[3.3.1]nonan-9-yl.

The heterocycle formed by R² and R³, or R⁴¹ and R⁴², or R⁵³ and R⁵⁴together with the adjacent nitrogen atom is exemplified by1-pyrrolidinyl, piperidino, homopiperidino, 1-piperazinyl, 1-piperazinylsubstituted by alkyl at the 4-position, morpholino and thiomorpholino.

Halogen means chlorine, bromine, fluorine and iodine.

Cycloalkylalkyl is that wherein cycloalkyl moiety has 3 to 10 carbonatoms and alkyl moiety has 1 to 6, preferably 1 to 3 carbon atoms and isexemplified by cyclopropylmethyl, 2,3-dimethylcyclopropylmethyl,cyclobutylmethyl, 3-methylcylobutylmethyl, cyclopentylmethyl,3,4-dimethylcyclopentylmethyl, cyclohexyl methyl,4-methylcylohexylmethyl, cycloheptylmethyl, cyclooctylmethyl,2-cyclohexylethyl, 3-cyclohexylpropyl, norbornylmethyl, 1-adamantylmethyl, bicyclo[3.3.0]octan-1-ylmethyl andbicyclo[3.3.1]nonan-9-ylmethyl.

Heteroaryl at R⁵ and R⁶ may have at least one hetero atom selected fromoxygen, sulfur and optionally substituted nitrogen as a ringconstituting atom and is a 5 to 7-membered ring which may be condensedwith aryl or heteroaryl optionally having, on the ring, theaforementioned substituent. Examples thereof include furyl, thienyl,pyrrolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl,pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, 2,3-dihydrobenzofuryl,benzopyranyl, benzimidazolyl, benzoxazolyl, quinolyl and benzoxazinyl,which may have, on the ring, to 3 substituents selected from halogen(chlorine, bromine, fluorine), alkyl (alkyl having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl,pentyl, isopentyl and hexyl), alkoxy (alkoxy having 1 to 6 carbon atomssuch methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy andhexyloxy), haloalkyl (that wherein alkyl moiety is alkyl having 1 to 4carbon atoms, such as chloromethyl, bromomethyl, fluoromethyl,trifluoromethyl, trifluoroethyl, pentafluoropropyl and chlorobutyl),hydroxy, nitro, amino, cyano, acyloxy (e.g. that wherein acyl moiety isalkanoyl having 2 to 5 carbon atoms, such as acetyl, propionyl, butyryland pivaloyl, or aroyl such as benzoyl which may have, on the ring, 1 to3 substituents selected from halogen (as defined above), alkyl (asdefined above), alkoxy (as defined above), haloalkyl (as defined above)and hydroxy, such as benzoyl, chlorobenzoyl, methylbenzoyl andmethoxybenzoyl).

Heteroarylalkyl may have, on the ring, 1 to 8 substituents selected fromhalogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, nitro, amino, cyanoand hydroxy and alkyl moiety has 1 to 4, preferably 1 to 2 carbon atomsand the hetero atom constituting the ring is nitrogen, oxygen or sulfur.Examples thereof include pyridyl(2-pyridyl, 3-pyridyl, 4-pyridyl)methyl,quinolyl(2-quinolyl, 3-quinolyl)methyl, indolyl(2-indolyl,3-indolyl)methyl, thienyl(2-thienyl, 3-thienyl)methyl, furyl(2-furyl,3-furyl)methyl, benzofuryl(2-benzofuryl, 3-benzofuryl)methyl,1H-benzimidazol-2-ylmethyl, 2-benzothiazolylmethyl, 2-(2-thienyl)ethyland 2-(2-furyl)ethyl.

Aryloxyalkyl is that wherein aryl moiety is phenyl and alkyl moiety isC1-C6 alkyl and is exemplified by phenoxymethyl, phenoxyethyl,phenoxypropyl, phenoxybutyl and phenoxyhexyl, which may have, on thering, 1 to 3 substituents selected from halogen (chlorine, bromine,fluorine), alkyl (alkyl having 1 to 6 carbon atoms such as methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, isopentyland hexyl), alkoxy (alkoxy having 1 to 6 carbon atoms such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and hexyloxy),haloalkyl (that wherein alkyl moiety is alkyl having 1 to 4 carbonatoms, such as chloromethyl, bromomethyl, fluoromethyl, trifluoromethyl,trifluoroethyl, pentafluoropropyl and chlorobutyl), hydroxy, nitro,amino, cyano and acyloxy (e.g. that wherein acyl moiety is alkanoylhaving 2 to 5 carbon atoms, such as acetyl, propionyl, butyryl andpivaloyl, or aroyl such as benzoyl which may have, on the ring, 1 to 3substituents selected from halogen (as defined above), alkyl (as definedabove), alkoxy (as defined above), haloalkyl (as defined above) andhydroxy, such as benzoyl, chlorobenzoyl, methylbenzoyl, methoxybenzoyl).

Haloalkyl is that wherein alkyl moiety has 1 to 5 carbon atoms and isexemplified by chloromethyl, bromomethyl, fluoromethyl, trifluoromethyl,trifluoroethyl, pentafluoropropyl and chlorobutyl.

Aryl may be, for example, phenyl, 1-naphthyl or 2-naphthyl which mayhave, on the aromatic ring, 1 to 3 substituents selected from halogen,C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, nitro, amino, cyano andhydroxy.

Heteroaryl may have, on the ring, 1 to 3 substituents selected fromhalogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, nitro, amino, cyanoand hydroxy and the hetero atom constituting the ring is nitrogen,oxygen or sulfur. Examples thereof include pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), quinolyl (2-quinolyl, 3-quinolyl), indolyl(2-indolyl, 3-indolyl), thienyl (2-thienyl, 3-thienyl), furyl (2-furyl,3-furyl), benzofuryl (2-benzofuryl, 3-benzofuryl), 1H-benzimidazol-2-yland 2-benzothiazolyl.

Alkoxy is exemplified by alkoxy having 1 to 6 carbon atoms, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentyloxy, isopentyloxy and hexyloxy.

Acyl is alkanoyl having 2 to 5 carbon atoms, such as acetyl, propionyl,butyryl and pivaloyl, or benzoyl.

Acyloxy is alkanoyloxy having 2 to 5 carbon atoms, such as acetyloxy,propionyloxy, butyryloxy and pivaloyloxy, or benzoyloxy.

Amino substituted by alkyl is amino mono- or di-substituted by alkylhaving 1 to 5 carbon atoms and is exemplified by methylamino,dimethylamino, ethylamino, diethylamino, propylamino and dipropylamino.

Cyclic amino is exemplified by pyrrolidinyl, piperidino, and morpholino,thiomorpholino and piperazinyl having, as a hetero atom, oxygen, sulfuror nitrogen atom wherein the nitrogen atom may be substituted by alkylor aralkyl.

Carbamoyl substituted by alkyl is carbamoyl mono- or di-substituted byalkyl having 1 to 5 carbon atoms and is exemplified by methylcarbamoyl,dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl anddipropylcarbamoyl.

Cyclic aminocarbonyl is that having the aforementioned cyclic aminomoiety and is exemplified by pyrrolidinylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazinylcarbonyl and4-methyl-1-piperazinylcarbonyl.

Alkoxycarbonyl is that wherein alkoxy moiety has 1 to 5 carbon atoms andis exemplified by methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl andtert-butoxycarbonyl.

Aralkyloxycarbonyl is that wherein alkoxy moiety has 1 to 5 carbon atomsand is exemplified by benzyloxycarbonyl, 2-phenylethoxycarbonyl and3-phenylpropoxycarbonyl, which may have halogen, nitro, alkyl, alkoxy,trifluoromethyl or the like as a substituent.

Alkylcarbonyl is that where alkyl moiety has 1 to 5 carbon atoms and isexemplified by acetyl, propionyl, butyryl, isobutyryl and pivaloyl.

Alkylene is exemplified by alkylene having 1 to 10 carbon atoms such asmethylene, ethylene, trimethylene, tetramethylene, hexamethylene,octamethylene and decamethylene, which may optionally have branchedchain and may be substituted by 1 to 3 hydroxys.

Alkenylene is exemplified by alkenylene having 2 to 8 carbon atoms andoptionally having branched chain, such as vinylene, propenylene,butynylene, hexenylene and octenylene; alkynylene is exemplified byalkynylene having 2 to 8 carbon atoms and optionally having branchedchain, such as ethynylene, propynylene, butynylene, hexynylene andoctynylene.

Aryloxy may be, for example, phenoxy or naphthyloxy.

Aralkyloxy is that wherein alkyl moiety has 1 to 6 carbon atoms and isexemplified by benzyloxy, 2-phenylethoxy and 3-phenylpropoxy.

Alkenyl or alkynyl having 2 to 18 carbon atoms which may be substitutedby 1 to 3 hydroxys is exemplified by 3-hydroxy-1-propenyl,3-methyl-3-hydroxy-1-butenyl, 3,4-dihydroxy-1-butenyl,3,4,5-trihydroxy-1-hexenyl, 3-hydroxy-1-propynyl, 1-hydroxy-2-butynyland 1,4-dihydroxy-2-butynyl.

Aralkenyl or aralkynyl having alkenyl moiety or alkynyl moiety having 2to 18 carbon atoms which may be substituted by 1 to 3 hydroxys isexemplified by 3-phenyl-1-propynyl, 3-phenyl-2-butenyl,3-(4-methylphenyl)-2-butenyl, 2-methyl-4-phenyl-1-butenyl,4-(4-methylphenyl)-1-butenyl, 4-phenyl-1-butenyl, 3-phenyl-1-propynyl,4-(3-methoxyphenyl)-2-butynyl, 4-phenyl-3-methyl-1-butynyl,4-phenyl-1-butynyl, 4-(4-methylphenyl)-1-butynyl and3-phenyl-3-hydroxy-1-butenyl, 3-phenyl-4-hydroxy-1-hexenyl,3-phenyl-3-hydroxy-1-propynyl, 3,4-dihydroxy-5-phenyl-1-pentynyl and4-(2-methylphenyl)-1-hydroxy-2-butynyl.

In the definitions for R²⁰, R²¹, R²² and R²³, a saturated or unsaturated3 to 7-membered ring formed combinedly with the adjacent nitrogen atom,which may be substituted by straight- or branched chain alkyl and whichmay have, in the ring, nitrogen, oxygen or sulfur atom as a hetero atom(the additional nitrogen atom being optionally substituted by straight-or branched chain alkyl having 1 to 4 carbon atoms, aralkyl ordiarylalkyl) is exemplified by 1-aziridinyl, 1-azetidinyl,1-pyrrolidinyl, piperidino, 1-piperazinyl, 1-azepinyl,1-perhydroazepinyl, morpholino, thiomorpholino, 1-imidazolyl,4-methyl-1-piperazinyl, 2,6-dimethylmorpholino, 1,2,4-triazol-1-yl,1-pyrazolyl, 1-pyrrolyl, 4-benzyl-1-piperazinyl, 4-benzylpiperidino,4-diphenylmethylpiperidino and 4-diphenylmethyl-1-piperazinyl.

Straight- or branched chain alkyl, alkenyl or alkynyl which may besubstituted by halogen, hydroxy, amino, alkylamino, dialkylamino, cyclicamino or C-bonded heterocycle (carbons may be interrupted by nitrogen,oxygen or sulfur) is exemplified by methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, octyl,decyl, vinyl, allyl, isopropenyl, 2-butenyl, ethynyl, 2-propynyl,chloromethyl, trifluoromethyl, 2-hydroxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-dimethylaminoethyl,2-morpholinoethyl, 2-piperidinoethyl, furfuryl, 2-(2-indolyl)-ethyl,2-thenyl, 2-pyridylmethyl, 2-quinolylmethyl and 2-pyrimidinylmethyl.

Straight- or branched chain alkylcarbonyl which may be mono- ordi-substituted by hydroxy, halogen, amino, alkylamino, dialkylamino,cyclic amino or straight- or branched chain alkyl (the alkyl may besubstituted by halogen or hydroxy) is exemplified by acetyl, propionyl,butyryl, isobutyryl and pivaloyl and those substituted by hydroxy,chlorine, amino, methylamino, dimethylamino, morpholino, methyl orethyl.

Arylcarbonyl means, for example, benzoyl, 4-hydroxybenzoyl,2-chlorobenzoyl or 4-methylbenzoyl.

Arylsulfonyl is, for example, phenylsulfonyl, 4-methylphenylsulfonyl,4-aminophenylsulfonyl or 4-acetylaminophenylsulfonyl.

Alkylsulfonyl is, for example, methanesulfonyl, ethanesulfonyl,propanesulfonyl or butanesulfonyl.

Arylcarbonyl at R²⁴ is, for example, benzoyl, thiazolylcarbonyl,imidazolylcarbonyl; alkyl having hydroxy and/or carbonyl may be, forexample, hydroxymethyl, 1-hydroxy-2-methylpropyl,3-hydroxy-2-methylpropyl, 1-hydroxyethyl, 2-hydroxy-2-methylpropyl orisobutyryl.

Heteroaryl which may be hydrogenated is monocyclic 5-, 6- or 7-memberedheterocyclic group or bicyclic or tricyclic group having one or morehetero atoms selected from nitrogen, oxygen and sulfur and said groupmay be substituted, preferably mono- or di-substituted by lower alkyl,lower alkoxy, oxo, hydroxy, chlorine or fluorine and is exemplified bythe groups of the following formulas. ##STR37##

A saturated or unsaturated 5-, 6- or 7-membered ring which is, togetherwith R¹⁷ and R¹⁸, condensed to thiophene ring is exemplified by##STR38##

Examples of cycloalkyl in cycloalkyl, cycloalkylcarbonyl,cycloalkoxycarbonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyland cycloalkylaminocarbonyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, which may be substituted byhalogen, alkyl, alkoxy, trifluoromethyl or phenyl.

When the compound of the present invention has one or more asymmetriccarbons, the present invention encompasses all racemates, diastereomersand individial optical isomers.

Most of the compounds of the formula (I) can be produced, separated andpurified by the methods described in the prior art references indicatedunder Background Art.

Of the compounds of formula (I), novel compounds can be produced by themethods described in the following.

Method 1

An aminoketone described in Japanese Patent Unexamined Publication No.256681/1990 ##STR39## wherein each symbol is as defined above, isreacted with a compound of the formula ##STR40## wherein Za¹ and Za² areeach hydrogen, an amino-protecting group such as tert-butoxycarbonyl orbenzyloxycarbonyl, or both combinedly form an amino-protecting groupsuch as phthaloyl and Za³ is a reactive group of hydroxy or carboxylsuch as halogen, a mixed anhydride-forming group and animidazolidide-forming group, to give an acyl compound, which is thendeprotected by a conventional method using hydrazine hydrate or thelike. The compound thus obtained of the formula ##STR41## wherein eachsymbol is as defined above, is subjected to a ring closure reaction withdehydration in an inert solvent such as ethanol, isopropyl alcohol,benzene or toluene in the presence of a weak acid such as acetic acid,propionic acid or silica gel at room temperature or under heating togive a compound of the formula (VII) ##STR42## wherein each symbol is asdefined above.

The compound (VII) can be led to a compound (VIII) by the methoddescribed in Japanese Patent Unexamined Publication No. 82/1989 or256681/1990. ##STR43## wherein each symbol is as defined above. TheCompound (VII) and the Compound (VIII) are encompassed in the Compound(IIA).

The reaction of a compound of the formula (IV) with a compound of theformula (V) and elimination of protecting group are carried outaccording to the method described, for example, in "Pepuchido Gosei noKiso to Jikken (Basic and Experiment of Peptide Synthesis)", NobuoIzumiya, Maruzen or "Protective Groups in Organic Synthesis", T. W.Green & P. G. Wuts, John Willey & Sons, Inc. These known referencesteach various amino-protecting groups inclusive of the exemplified aboveand those are also usable in the present invention.

Method 2 ##STR44## wherein each symbol is as defined above.

For example, the above-mentioned Compound (IX) is reacted with acompound of the formula (X)

    Hal-(CH.sub.2)aN(R.sup.33)(R.sup.34)                       (X)

wherein Hal means halogen and other symbols are as defined above, in aninert solvent such as methanol, ethanol, propanol, isopropyl alcohol ordimethylformamide in the presence of sodium hydride, lithium hydride,potassium carbonate, sodium carbonate, sodium methoxide or sodiumethoxide to give a compound of the aforementioned formula (IIIA).

A compound (IV') wherein R¹⁵ ' is alkyl having 8 to 15 carbon atoms oraralkyl, which is the starting compound (IIB), is produced by thefollowing method.

Haloalkyl of the formula

    R.sup.15 "--(CH.sub.2)-Hal                                 (XI)

wherein R¹⁵ " is alkyl or aralkyl having a carbon number less 2 fromthat of the aforementioned R¹⁵ ', is reacted with triphenylphosphine inan inert solvent such as toluene, chloroform or tetrahydrofuran andthereto is added a base such as n-butyl lithium to give phosphorane. Thephosphorane is reacted with p-nitrobenzaldehyde (Wittig reaction) togive a compound of the formula ##STR45## wherein each symbol is asdefined above. Then, the compound is subjected to reduction in thepresence of an acid such as acetic acid or hydrochloric acid with 1-5atm hydrogen to give a compound of the formula ##STR46## wherein eachsymbol is as defined above. Thereto are added benzonitrile, aluminumchloride and boron trichloride to allow reaction to give a compound ofthe formula ##STR47## wherein each symbol is as defined above. Method 3

A compound of the formula (I) wherein W is --O--, and X and Y combinedlyform ═N--N═C(R⁶)--, which is represented by the formula ##STR48##wherein each symbol is as defined above, is synthesized, for example, bythe following methods.

Method A

An aminoketone of the formula ##STR49## wherein each symbol is asdefined above, is reacted with (a) a compound of the formula ##STR50##wherein Z¹ and Z² are the same or different and each is halogen such aschlorine or bromine and R and R' are as defined above, in a solvent suchas acetone, tetrahydrofuran or dioxane under cooling, at roomtemperature or under heating to give an N-haloacetyl compound. TheN-haloacetyl compound is reacted with potassium iodide or sodium iodideas necessary to convert same to an N-iodoacetyl compound which is thenreacted with ammonia to give an N-glycyl compound of the formula##STR51## wherein each symbol is as defined above; or (b) a compound ofthe formula ##STR52## wherein Z³ is halogen such as chlorine or bromineand R and R' are as defined above, to give an acetyl compound, followedby deprotection by a conventional method using hydrazine hydrate, etc.to give a compound of the formula (10).

The N-glycyl compound thus obtained is subjected to a ring closurereaction with dehydration in a solvent inert to the reaction, such asethanol, propanol, isopropyl alcohol, butanol, benzene, toluene,dimethylformamide or dimethylacetamide, preferably in the presence of aweak acid catalyst such as acetic acid, propionic acid or silica gel atroom temperature or under heating to give a compound of the formula##STR53## wherein each symbol is as defined above. A thionating agent isreacted with the compound of the formula (12) to give a compound of theformula ##STR54## wherein each symbol is as defined above. Further, (a)a compound of the formula (13) is reacted with a compound of the formula

    R.sup.6 CONHNH.sub.2                                       ( 14)

wherein R⁶ is as defined above, to give a triazolodiazepine compound ofthe formula ##STR55## wherein each symbol is as defined above.Alternatively, (b) a compound of the formula ##STR56## wherein eachsymbol is as defined above, which is obtained by reacting a compound ofthe formula (13) with a hydrazine hydrate, is reacted with a compound ofthe formula

    R.sup.6 COOH                                               (16)

wherein R⁶ is as defined above, or a reactive derivative thereof or acompound of the formula

    R.sup.6 C(OR.sup.62).sub.3                                 ( 17)

wherein R⁶² is alkyl having 1 to 5 carbon atoms such as methyl or ethyland R⁶ is as defined above, to give a compound of the formula (3-a).

In the above-mentioned methods, the thionating reagent may be, forexample, phosphorus pentasulfide, Lawesson's reagent[2,4-bis(4-methoxyphenyl)1,3,2,4-dithiadiphosphetane-2,4-disulfide] orthe like and the reactive derivative of the compound of the formula (16)may be, for example, carboxylic acid halide (carboxylic acid chloride,carboxylic acid bromide), carboxylic acid anhydride, mixed anhydride(lower alkyl carboxylic acid mixed anhydride, alkyl phosphoric acidmixed acid anhydride), lower alkyl ester (methyl ester, ethyl ester),activated ester (benzyl ester, p-nitrobenzyl ester, p-nitrophenyl ester,p-chlorophenyl ester) or the like.

The reaction of a compound of the formula (12) with a thionating reagentproceeds in a solvent inert to the reaction, such as pyridine,dimethylaniline, benzene, toluene, xylene, tetrahydrofuran, chloroform,dichloromethane, dioxane or mixed solvent thereof at 30°-100° C.

The reaction of a compound of the formula (13) with a compound of theformula (14) proceeds in a solvent inert to the reaction, such asbenzene, toluene, xylene, tetrahydrofuran, dioxane, methanol, ethanol,propanol or isopropyl alcohol in the presence of an organic acid such asacetic acid or propionic acid, inorganic acid such as hydrochloric acidor sulfuric acid, or silica gel at room temperature to the refluxingtemperature of the solvent used.

The reaction of a compound of the formula (13) with hydrazine or ahydrate thereof generally proceeds in a solvent inert to the reaction,such as methanol, ethanol, propanol, isopropyl alcohol, butanol ortetrahydrofuran at 0°-40° C.

The reaction of a compound of the formula (15) with a compound of theformula (16) or a reactive derivative thereof or a compound of theformula (17) proceeds in a solvent inert to the reaction, such asbenzene, toluene, xylene, tetrahydrofuran or dioxane, preferably in thepresence of an organic acid such as acetic acid or propionic acid,inorganic acid such as hydrochloric acid, sulfuric acid or phosphoricacid, or silica gel at room temperature to the refluxing temperature ofthe solvent used.

The obtained compound of the formula (3-a) is hydrolyzed with aninorganic acid such as hydrochloric acid or sulfuric acid and reactedwith an aqueous solution of nitrous acid to give a compound of theformula ##STR57## wherein each symbol is as defined above.

A compound of the formula (4-a) is dissolved in a suitable solvent suchas methanol or ethanol and reduced with a suitable reducing agent suchas sodium borohydride, sodium cyanoborohydride or lithium aluminumhydride to give a compound of the formula ##STR58## wherein each symbolis as defined above.

The compound of the formula (18) is subjected to a ring closure reactionwith dehydration in an inert solvent such as benzene, toluene or xylene,preferably in the presence of a strong acid catalyst such ashydrochloric acid or sulfuric acid under heating to give a compound ofthe formula (1-a).

Method B

A compound of the formula (1-a) wherein R⁶ is R⁴³ CONH(CH₂)a-- whereineach symbol is as defined above is synthesized by the following method.

A compound of the formula (15) obtained by the Method A is reacted witha compound of the formula

    Am(CH.sub.2)aCOZ.sup.4                                     ( 19)

wherein Am is amine protected with a protecting group such asphthalimido, 2,3-diphenylmaleimido or dithiasuccinimido, Z⁴ is halogensuch as chlorine or bromine and a is as defined above, to give an acetylcompound.

The obtained acetyl compound is subjected to a ring closure reactionwith dehydration in a solvent inert to the reaction, such as ethanol,propanol, isopopyl alcohol, butanol, benzene, toluene dimethylformamideor dimethylacetamide, preferably in the presence of a weak acid catalystsuch as acetic acid, propionic acid or silica gel at room temperature orunder heating, followed by deprotection by a conventional method to givea compound of the formula ##STR59## wherein each symbol is as definedabove.

The obtained compound of the formula (20) is reacted with a compound ofthe formula

    R.sup.43 COOH                                              (21)

wherein R⁴³ is as defined above, or a reactive derivative thereof in asolvent inert to the reaction, such as benzene, toluene, xylene,tetrahydrofuran or dioxane at room temperature to the refluxingtemperature of the solvent used, to give a compound of the formula##STR60## wherein each symbol is as defined above.

This compound is subjected to a series of reactions for forming atriazoloxazepine ring, as described in the Synthesis Method A for thecompound of the formula (1-a) to give a triazole compound of the formula##STR61## wherein each symbol is as defined above, from which theobjective compound is obtained.

Method 4

A compound of the formula (I) wherein R is of the formula (3), (16) or(17) is produced by an addition reaction of isocyanate or isothiocyanateof the formula

    R.sup.63 --N═C═Z                                   (XV)

wherein R⁶³ is R¹¹, R¹², --CORa¹¹ or --SO₂ Ra¹¹, and R¹¹, R¹², Ra¹¹ andZ are as defined above, to a compound of the formula ##STR62## whereineach symbol is as defined above, or a compound of the formula (I)wherein R is of the formula (3) is produced by condensing a compound ofthe formula (XIV) with a compound of the formula

    R.sup.11 COG                                               (XVI)

wherein R¹¹ is as defined above and G is a leaving group such ashydroxy, halogen, ester (e.g. pentachlorophenoxy, p-nitrophenoxy) orthioester (e.g. phenylthio, 2,6-dimethylpyridine-4-thio).

The addition reaction of a compound of the formula (XIV) and a compoundof the formula (XV) is carried out in a suitable solvent which does notinterfere with the reaction. Examples of the solvent include organicsolvents such as tetrahydrofuran, diethyl ether, diisopropyl ether,dioxane, dichloromethane, chloroform, carbon tetrachloride, ethylacetate, benzene, toluene, xylene, dimethylformamide anddimethylacetamide. While the reaction temperature varies depending onthe reagent and solvent to be used, it is generally from -20° C. to theboiling point of the solvent.

The condensation reaction of a compound of the formula (XIV) and acompound of the formula (XVI) is carried out in a suitable solventaccording to the conventional peptide synthesis method as described inMethod 1. Examples of the solvent include organic solvents such astetrahydrofuran, diethyl ether, diisopropyl ether, dioxane,dichloromethane, chloroform, carbon tetrachloride, ethyl acetate,benzene, toluene, xylene, dimethylformamide and dimethylacetamide. Wherenecessary, the reaction is carried out in the presence of a base or adehydrative condensing agent at a temperature of from -20° C. to theboiling point of the solvent.

Examples of the base to be used as necessary include alkaline metalhydroxides (sodium hydroxide, potassium hydroxide), alkaline metalcarbonates (sodium carbonate, potassium carbonate), alkaline metalhydrogencarbonates (sodium hydrogencarbonate, potassiumhydrogencarbonate), alkaline metal hydrides (sodium hydride) and organicbase (triethylamine, pyridine, picoline, N-methylmorpholine). Wherenecessary, alkaline metal hydroxide may be used in two phases of theabove-mentioned organic solvent and water by using a phase transfercatalyst such as tetrabutylammonium bromide or benzyltriethylammoniumiodide. Examples of the dehydrative condensing agent include those usedfor amide synthesis, such as dicyclohexylcarbodiimide,N-ethyl-N'-(3-dimethylaminomethyl)carbodiimide hydrochloride,diphenylphosphoryl azide and N-methyl-2-chloropyridinium iodide.

Method 5

A compound of the formula (XIV) wherein b is 0, which is represented bythe formula ##STR63## wherein each symbol is as defined above, can beobtained as follows.

A compound of the formula ##STR64## wherein each symbol is as definedabove, is reacted with dialkyl carbonate such as diethyl carbonate inthe presence of a base such as sodium hydride, potassium t-butoxide,lithium diisopropylamide or butyl lithium to introduce alkoxycarbonylsuch as ethoxycarbonyl at the 6-position and the obtained compound isreacted with O-(2,4-dinitrophenyl)hydroxylamine to give a compound ofthe formula ##STR65## wherein R⁶⁴ is alkyl such as ethyl and othersymbols are as defined above, and the compound of the formula (XVIII) issubjected to hydrolysis in water or a mixed solvent of water and anorganic solvent such as methanol, ethanol, diethyl ether,tetrahydrofuran or dioxane in the presence of a base such as sodiumhydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide ata temperature of from about 0° C. to the boiling point of the solventused, and the obtained reaction mixture is subjected to decarboxylationby converting same to acidic with an acid such as hydrochloric acid,sulfuric acid, hydrobromic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid to give a compound of the formula##STR66## wherein each symbol is as defined above, and the obtainedcompound is reacted with an alkyl halide of the formula

    R.sup.10 -Hal                                              (XX)

wherein Hal is halogen and R¹⁰ is as defined above, in a suitablesolvent such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, benzene, toluene, xylene or dimethylformamide in the presenceof a base such as sodium hydride, potassium t-butoxide, lithiumdiisopropylamide, butyl lithium, pyridine, triethylamine, potassiumcarbonate, sodium carbonate or sodium hydrogencarbonate at a temperatureof from -20° C. to the boiling point of the solvent used, or reactedwith an aldehyde in the presence of a reducing agent such as sodiumborohydride or sodium cyanoborohydride.

Method 6

A compound of the formula (XIV) wherein b is 1-6 is obtained as follows.After introducing alkoxycarbonyl in the same manner as in the case ofthe compound of the aforementioned formula (XVIII), a compound of theformula ##STR67## wherein b' is an integer of 1 to 6 and Hal is halogen,is reacted with the compound obtained in the above to give a compound ofthe formula ##STR68## wherein Phth means phthaloyl and other symbols areas defined above, and the compound of the formula (XXII) is subjected tohydrolysis in water or a mixed solvent of water and an organic solventsuch as methanol, ethanol, diethyl ether, tetrahydrofuran or dioxane inthe presence of a base such as sodium hydroxide, potassium hydroxide,barium hydroxide or lithium hydroxide at a temperature of from about 0°C. to the boiling point of the solvent used, and the obtained reactionmixture is subjected to decarboxylation by converting same to acidicwith an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid,trifluoroacetic acid or trifluoromethanesulfonic acid, and the obtainedcompound is deprotected in a suitable solvent such as water, methanol,ethanol, isopropyl alcohol, tetrahydrofuran, dioxane or a mixed solventthereof by adding hydrazine at a temperature of from about 0° C. to theboiling point of the solvent used to give a compound of the formula##STR69## wherein each symbol is as defined above, and the obtainedcompound is reacted with an alkyl halide of the formula (XX) in asuitable solvent such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, benzene, toluene, xylene or dimethylformamidein the presence of a base such as sodium hydride, potassium t-butoxide,lithium diisopropylamide, butyl lithium, pyridine, triethylamine,potassium carbonate, sodium carbonate or sodium hydrogencarbonate at atemperature of from -20° C. to the boiling point of the solvent used, orreacted with an aldehyde in the presence of a reducing agent such assodium borohydride or sodium cyanoborohydride.

A compound of the formula (XXIII) wherein b' is 1, which is representedby the formula ##STR70## can be produced by the following method.

A compound of the formula ##STR71## wherein each symbol is as definedabove, is condensed with 2,3-diaminopropionic acid wherein an aminogroup has been protected as necessary, according to the conventionalpeptide synthesis method described in Method 1 and deprotected to give acompound of the formula ##STR72## wherein each symbol is as defined,above and the amino at the 3-position may be protected as necessary. Theobtained compound is subjected to a ring closure reaction withdehydration in an inert solvent such as ethanol, isopropanol, benzene ortoluene in the presence of a weak acid such as acetic acid, propionicacid or silica gel at room temperature or under heating to give acompound of the formula ##STR73## wherein each symbol is as definedabove. According to the similar method as Method A in the aforementionedMethod 3, a 5-membered ring can be formed in the obtained compound.

Method 7

A compound of the formula (XVII) wherein X and Y combinedly form═N--N═C(R⁶)-- is produced by reacting a compound obtained according toJapanese Patent Unexamined Publication No. 79185/1989 or 156982/1989,which has the formula ##STR74## wherein each symbol is as defined above,with a compound of the formula

    R.sup.6 CONHNH.sub.2                                       (XXV)

wherein R⁶ is as defined above, or by reacting a compound obtained byreacting a compound of the formula (XXIV) with a hydrazine hydrate,which has the formula ##STR75## wherein each symbol is as defined above,with a compound of the formula

    R.sup.6 COOH                                               (XXVII)

wherein R⁶ is as defined above, or a reactive derivative thereof, or acompound of the formula

    R.sup.6 C(OR.sup.65).sub.3                                 (XXVIII)

wherein R⁶⁵ is alkyl such as methyl or ethyl and R⁶ is as defined above.

The reaction of a compound of the formula (XXIV) with a hydrazinehydrate usually proceeds in a solvent inert to the reaction such asmethanol, ethanol, propanol, isopropyl alcohol or butanol at 0°-40° C.for 5 minutes to 3 hours.

The reaction of a compound of the formula (XXVI) with a compound of theformula (XXVII) or a reactive derivative thereof or a compound of theformula (XXVIII) proceeds in a solvent inert to the reaction such asbenzene, toluene, xylene, tetrahydrofuran, dioxane or a mixed solventthereof in the presence of an organic acid such as acetic acid orpropionic acid, an inorgnic acid such as hydrochloric acid or sulfuricacid, or silica gel at a temperature of from room temperature to therefluxing temperature of the solvent used for 30 minutes to 6 hours.

Method 8

A compound of the formula (XVII) wherein X and Y combinedly form═N--C(R⁵)═C(R⁶)-- is produced by reacting a compound of the formula(XXIV) with a compound of the formula ##STR76## wherein R⁶⁶ is alkylsuch as methyl or ethyl, or aralkyl such as benzyl and R⁶ and R⁵ are asdefined above.

The reaction usually proceeds in a solvent inert to the reaction such asmethanol, ethanol, dioxane, dimethylformamide, tetrahydrofuran, benzene,toluene, xylene or a mixed solvent thereof in the presence of an acidcatalyst such as mineral acid (e.g. hydrochloric acid, sulfuric acid,polyphosphoric acid), lower fatty acid (e.g. formic acid, acetic acid,propionic acid), or organic sulfonic acid (e.g. methanesulfonic acid,p-toluenesulfonic acid) at a temperature of from room temperature to150° C., preferably while refluxing the solvent. When the acid catalystitself which is used in the above reaction is liquid, it may act as asolvent. When a solvent is not used, the reaction is carried out at atemperature somewhat higher than the melting point of the compound ofthe formula (XVII), generally 150°-220° C.

Method 9

A compound of the formula ##STR77## wherein each symbol is as definedabove, can be obtained by reacting a compound of the formula ##STR78##wherein each symbol is as defined above, with a sulfonyl halide of theformula

    Hal-SO.sub.2 R.sup.44                                      (IIIb)

wherein Hal is halogen such as chlorine and other symbols are as definedabove, in an inert solvent such as dichloromethane, chloroform, benzene,toluene, carbon tetrachloride, tetrahydrofuran or dioxane in thepresence of, where necessary, a base such as triethylamine, pyridine orN-methylmorpholine.

Method 10

A compound of the formula ##STR79## wherein each symbol is as definedabove, is obtained by reacting a compound of the formula (IIb) with ahalide of the formula

    Hal-COOR.sup.45                                            (IVb)

wherein each symbol is as defined above, in an inert solvent such aschloroform, dichloromethane, benzene, toluene, dimethylformamide,tetrahydrofuran or dioxane.

Method 11

A compound of the formula ##STR80## wherein each symbol is as definedabove, is obtained by reacting a compound of the formula ##STR81##wherein each symbol is as defined above, with a halide of the formula

    Hal-CZN(R.sup.11)(R.sup.12)                                (VIb)

wherein each symbol is as defined above, or an isocyanate or anisothiocyanate of the formula

    Z═C═N--R.sup.67                                    (VIIb)

wherein R⁶⁷ is either R¹¹ or R¹², in an inert solvent such asdichloromethane, chloroform, benzene, toluene, dimethylformamide orcarbon tetrachloride.

Method 12

A compound of the formula ##STR82## wherein each symbol is as definedabove, is obtained by reacting a compound of the formula ##STR83## wherein each symbol is as defined above, with a compound of the formula

    HN(R.sup.47)(R.sup.48)                                     (IXb)

where in each symbol is as defined above.

The reaction is carried out according to the conventional peptidesynthesis method as previously described in Method 1, in a suitablesolvent such as an organic solvent (e.g. tetrahydrofuran, diethyl ether,diisopropyl ether, dioxane, dichloromethane, chloroform, carbontetrachloride, ethyl acetate, benzene, toluene, xylene,dimethylformamide or dimethylacetamide) in the presence of a base or adehydrative condensing agent as necessary at a temperature of from -20°C. to the boiling point of the solvent. Examples of the base to be usedas necessary include triethylamine, pyridine and N-methylmorpholine. Thedehydrative condensing agent is preferably that conventionally used forpeptide synthesis, such as dicyclohexylcarbodiimide,N-ethyl-N'-(3-dimethylaminomethyl)carbodiimide hydrochloride,diphenylphospholyl azide, N-methyl-2-chloropyridinium iodide ormolecular sieves.

Method 13

A compound of the formula ##STR84## wherein each symbol is as definedabove, can be obtained by reacting a compound of the formula (Vb) withan acid halide of the formula

    Hal-COR.sup.46                                             (Xb)

wherein each symbol is as defined above, or an acid anhydride of theformula

    (R.sup.46 CO).sub.2 O                                      (XIb)

wherein each symbol is as defined above, in an inert solvent such asdichloromethane, chloroform, benzene, toluene, dimethylformamide orcarbon tetrachloride.

Method 14

A compound of the formula ##STR85## wherein each symbol is as definedabove, can be obtained by reacting a compound of the formula (Vb) with acompound of the formula

    Hal-SO.sub.2 R.sup.44                                      (XIIb)

where in each symbol is as defined above.

Method 15

A compound of the formula ##STR86## wherein R⁶⁸ is alkyl such as methylor ethyl and other symbols are as defined above, is obtained by reactinga compound of the formula ##STR87## wherein each symbol is as definedabove, with dialkyl carbonate such as diethyl carbonate in the presenceof a base such as sodium hydride, potassium t-butoxide, lithiumdiisopropylamide or butyl lithium to introduce alkoxycarbonyl at the3-position. Then, the compound is reacted with a halide of the formula

    Hal-(CH.sub.2)bCOR.sup.49                                  (XIVb)

wherein each symbol is as defined above, and the obtained compound ofthe formula ##STR88## wherein each symbol is as defined above, ishydrolyzed in water or a mixed solvent of water and a suitable solventsuch as methanol, ethanol, tetrahydrofuran or dioxane in the presence ofa base such as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogencarbonate or barium hydroxide at atemperature of from 0° C. to the boiling point of the solvent used, andthen subjected to decarboxylation with an acid such as hydrochloricacid, sulfuric acid, hydrobromic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid to give a compound of the formula##STR89## wherein each symbol is as defined above. Method 16

A compound of the formula ##STR90## wherein each symbol is as definedabove, is obtained by halogenating a compound of the formula (Vb) byreacting same with a halogenating agent such as phosphorus oxychloride,phosphorus tribromide, chlorine, bromine or N-bromosuccinimide in aninert solvent such as dichloromethane, chloroform, carbon tetrachloride,benzene, toluene, dioxane or dimethylformamide, and reacting thehalogenated compound with thiol or thiolate of the formula

    R.sup.11 SH or R.sup.11 SNa                                (XVIb)

wherein R¹¹ is as defined above, in a suitable solvent such as methanol,ethanol, dimethylacetamide or dimethylformamide. The obtained compoundis oxidized with an oxidizing agent such as hydrogen peroxide, potassiumpermanganate, sodium hypochlorite, ozone or ruthenium oxide in ethanol,methanol, acetic acid or a mixed solvent of acetic acid and water togive a compound of the formula ##STR91## wherein n' is 1 or 2 and othersymbols are as defined above. Method 17

A compound of the formula ##STR92## wherein each symbol is as definedabove, is obtained by reacting a compound of the formula (IIb) withCOCl₂ (phosgene) in an organic solvent such as toluene, chloroform ortetrahydrofuran in the presence of an organic base such as triethylamineat room temperature or under ice-cooling and 30 minutes to 1 hour later,adding an amine of the formula

    HN(R.sup.11)(R.sup.12)                                     (Ie)

wherein each symbol is as defined above.

Note that a compound of the formula (D-I) can be also obtained byreacting COCL₂ with a compound of the formula (Ie) and then with acompound of the formula (IIb).

In the same manner as above, a compound of the formula ##STR93## whereineach symbol is as defined above, is obtained by the use of (COCl)₂(oxalyl chloride) in place of COCl₂ (phosgene).

Method 18

A compound of the formula ##STR94## wherein each symbol is as definedabove, is obtained by adding a hydrazine of the formula

    HN(R.sup.10)N(R.sup.10)(R.sup.11)

wherein R¹⁰ and R¹¹ are as defined above, to a compound of the formula(XIIIb') in a polar solvent such as dimethyl sulfoxide ordimethylformamide at a temperature of from 0° C. to the boiling point ofthe solvent used.

Method 19

A compound of the formula ##STR95## wherein each symbol is as definedabove, is obtained by adding an acid chloride of the formula

    Cl--CZ--Ra.sup.11

wherein Ra¹¹ and Z are as defined above, to a compound of the formula(D-III) wherein R¹¹ is hydrogen in an inert solvent such as toluene,chloroform or tetrahydrofuran in the presence of an organic base such astriethylamine at a temperature of from 0° C. to the boiling point of thesolvent used.

By a similar method, a compound of the formula ##STR96## wherein eachsymbol is as defined above, is obtained by the use of Cl--SO₂ --Ra¹¹ inplace of Cl--CZ--Ra¹¹.

Method 20

A compound of the formula ##STR97## wherein each symbol is as definedabove, is obtained by reacting a compound of the formula (D-III) whereinR¹¹ is hydrogen with a nitrite such as isopentyl nitrite in a polarsolvent such as dimethyl sulfoxide or dimethylformamide in the presenceof an acid such as anhydrous hydrochloric acid at a temperature not morethan -10° C., preferably between -40° C. and -30° C., and 30 minutes to1 hour later, reacting the obtained compound with an amine of theformula

    HN(R.sup.47)(R.sup.48)

wherein each symbol is as defined above, at a temperature not more than-50° C., preferably not more than -70° C., and gradually raising thetemperature of the reaction mixture to 0° C. immediately thereafter.

Method 21

A compound of the formula ##STR98## wherein each symbol is as definedabove, is obtained by reacting a compound of the formula (D-III) whereinR¹¹ is hydrogen with an alkyl halide of the formula

    Ra.sup.11 -CH.sub.2 -Hal

wherein each symbol is as defined above, in a suitable solvent such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, benzene,toluene, xylene or dimethylformamide in the presence of a base such assodium hydride, potassium tert-butoxide, lithium diisopropylamide, butyllithium, pyridine, triethylamine, potassium carbonate, sodium carbonateor sodium hydrogencarbonate at a temperature of from 20° C. to theboiling point of the solvent used, or with an aldehyde in the presenceof a reducing agent such as sodium borohydride or sodiumcyanoborohydride.

Method 22

A compound of the formula ##STR99## wherein each symbol is as definedabove, is obtained by reacting a compound of the formula ##STR100##wherein each symbol is as defined above, with a compound of the formula##STR101## wherein Z¹ is an amino-protecting group except phthaloyl,such as tert-butoxycarbonyl or benzyloxycarbonyl, or hydrogen, accordingto method 6. The protecting group Z¹ is eliminated by a conventionalmethod and reacted with a compound of the formula

    O═C═N--R.sup.12

wherein R¹² is as defined above, according to Method 4 to give acompound of the formula ##STR102## wherein each symbol is as definedabove. This compound is subjected to ring closure reaction, for example,by adding sodium hydride and raising the temperature of the reactionmixture to 70° C. to give a compound of the formula ##STR103## whereineach symbol is as defined above. Method 23

A compound of the present invention having the following formula whereinthe double bond between carbon and nitrogen is reduced can be obtainedby a reduction method generally known, which is exemplified in thefollowing. ##STR104##

Exemplified are a method of catalytic hydrogenation with hydrogen in thepresence of a metal catalyst such as Raney-nickel, palladium black orplatinum oxide, a method by the use of a metal hydride such as sodiumborohydride, sodium cyanoborohydride or lithium borohydride and a methodby a reduction with formic acid or formalin, preferably with zinc inacetic acid.

Method 24

A compound of the formula (I) wherein W is --S-- can be synthesizedaccording to the method described in Japanese Patent UnexaminedPublication No. 66585/1992.

[Production of Intermediate]

A compound of the formula (IIb) wherein b is 0 can be obtained byreacting a compound of the formula ##STR105## wherein each symbol is asdefined above, which is obtained by the method described in JapanesePatent Unexamined Publication No. 28181/1990, with an alkyl halide ofthe formula

    R.sup.10 '-Hal                                             (XVIIIb)

wherein R¹⁰ ' is R¹⁰ other than hydrogen and Hal is as defined above, ina suitable solvent such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, benzene, toluene, xylene or dimethylformamidein the presence of a base such as sodium hydride, potassiumtert-butoxide, lithium diisopropylamide, butyl lithium, pyridine,triethylamine, potassium carbonate, sodium carbonate or sodiumhydrogencarbonate at a temperature of from -20° C. to the boiling pointof the solvent used, or with an aldehyde in the presence of a reducingagent such as sodium borohydride or sodium cyanoborohydride.

A compound of the formula (IIb) wherein b is 1 to 6 can be synthesizedby the following synthesis steps. ##STR106## wherein R⁶⁸ is alkyl suchas methyl or ethyl, Phth is phthaloyl and other symbols are as definedabove.

A compound of the formula (XIIIb) is reacted with dialkyl carbonate suchas diethyl carbonate in the presence of a base such as sodium hydride,potassium tert-butoxide, lithium diisopropylamide or butyl lithium tointroduce alkoxycarbonyl group such as ethoxycarbonyl at the 3-positionand the obtained compound is reacted with a halide of the formula:Hal(CH₂)aNPhth wherein Phth is phthaloyl and other symbols are asdefined above, to give a compound of the formula (XIXb). The compound ofthe formula (XIXb) is hydrolyzed in water or a mixed solvent of waterand an organic solvent such as, preferably, methanol, ethanol, diethylether, tetrahydrofuran or dioxane in the presence of a base such assodium hydroxide, potassium hydroxide, barium hydroxide or lithiumhydroxide at a temperature of from about 0° C. to the boiling point ofthe solvent used, and the obtained compound is subjected todecarboxylation by making the reaction mixture acidic with an acid suchas hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroaceticacid or trifluoromethanesulfonic acid and then deprotected in a suitablesolvent such as water, methanol, ethanol, isopropyl alcohol,tetrahydrofuran, dioxane or a mixed solvent thereof by adding hydrazineat a temperature of from about 0° C. to the boiling point of the solventused to give a compound of the formula (XXb). The compound of theformula (XXb) is reacted with an alkyl halide of the formula (XVIIIb) ina suitable solvent such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, benzene, toluene, xylene or dimethylformamidein the presence of a base such as sodium hydride, potassiumtert-butoxide, lithium diisopropylamide, butyl lithium, pyridine,triethylamine, potassium carbonate, sodium carbonate or sodiumhydrogencarbonate at a temperature of from -20° C. to the boiling pointof the solvent used, or with an aldehyde in the presence of a reducingagent such as sodium borohydride or sodium cyanoborohydride to give acompound of the formula (IIb).

A compound of the formula (Vb) wherein a is 0 can be synthesized by thefollowing synthesis steps. ##STR107## wherein each symbol is as definedabove.

A compound of the formula (XIIIb) is converted to N-oxide (XXIb) with aperacid such as m-chloroperbenzoic acid, hydrogen peroxide or peraceticacid in an inert solvent such as chloroform, carbon tetrachloride,dichloroethane, benzene or toluene, and the N-oxide is subjected toPolonovski rearrangement in acetic anhydride to give a compound of theformula (XXIIb). The compound of the formula (XXIIb) is hydrolyzed bythe reaction with a base such as sodium hydroxide, barium hydroxide orpotassium hydroxide in a mixed solvent of water and a suitable organicsolvent such as methanol, ethanol or isopropanol to give a compound ofthe formula (V'b).

A compound of the formula (Vb) wherein b is 1 to 6 can be obtained byintroducing an alkoxycarbonyl at the 3-position of a compound of theformula (XIIIb) in the same manner as described above, reacting theobtained compound with a halide of the formula

    Hal-(CH.sub.2)bOCOR.sup.62                                 (XXIIIb)

wherein R⁶² is alkyl such as methyl or ethyl and other symbols are asdefined above, to give a compound of the formula ##STR108## wherein eachsymbol is as defined above, and subjecting the compound todecarboxylation and hydrolysis as mentioned above.

A compound of the formula (lib) or (Vb) wherein b is 1 to 6 can be alsodirectly obtained by reacting a compound of the formula (XIIIb) with acompound of the formula: Hal-(CH₂)bNPhth or Q--(CH₂)bOCOR' wherein eachsymbol is as defined above, in an intert solvent such astetrahydrofuran, dioxane, diethyl ether, benzene, toluene ordimethylformamide in the presence of a base such as sodium hydride,potassium tert-butoxide, lithium diisopropylamide or butyl lithium. Thereaction generally proceeds at a temperature of from -50° C. to not morethan 0° C. and the obtained compound is respectively deprotected andhydrolyzed to give a compound of the formula (IIb) or (Vb).

A compound of the formula (VIIIb) can be synthesized by the followingsynthesis steps. ##STR109## wherein each symbol is as defined above.

A compound of the formula (XIIIb) is reacted with dialkyl carbonate suchas diethyl carbonate in the presence of a base such as sodium hydride,potassium tert-butoxide, lithium diisopropylamide or butyl lithium tointroduce alkoxycarbonyl such as ethoxycarbonyl at the 3-position ofdiazepine ring and then reacted with a haloester of the formula

    Hal-(CH.sub.2)bCOOR.sup.62

wherein R⁶², Hal and b are as defined above, to give a compound of theformula (XXVIb). The compound of the formula (XXVIb) is hydrolyzed inwater or a mixed solvent of water and a suitable solvent such asmethanol, ethanol, tetrahydrofuran or dioxane in the presence of a basesuch as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogencarbonate or barium hydroxide at atemperature of from 0° C. to the boiling point of the solvent used andthe obtained compound is subjected to decarboxylation by converting thereaction mixture to acidic with an acid such as hydrochloric acid,sulfuric acid, hydrobromic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid to give a compound of the formula (VIIIb).

The compounds of the formula (I) thus obtained can be separated andpurified from a reaction mixture by a method known per se such asrecrystallization and column chromatography.

The compounds of the formula (I) thus obtained can be converted topharmaceutically acceptable salts by a conventional method by treatingwith an inorganic acid such as hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid or nitric acid, an organic acid such asacetic acid, propionic acid, succinic acid, glycolic acid, lactic acid,malic acid, tartaric acid, citric acid, maleic acid, fumaric acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid orascorbic acid, an inorganic base such as sodium hydroxide, potassiumhydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide orammonium hydroxide, an organic base such as methylamine, diethylamine,triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)aminomethane, quinine, guanidine or cinchonine or anamino acid such as lysine, ornithine, arginine or alanine. The compoundsof the formula (I) encompass hydrates and other solvates.

When the compounds of the present invention have chiral carbon atom,they can be usually obtained as racemates. The racemates can be resolvedinto optical isomers by conventional methods. Such optical isomers canbe also produced by using optically active starting materials.Individual diastereomers can be purified by fractional crystallizationor chromatography.

In the present invention, the compounds of the formula (I) encompass thefollowing compounds.

Each symbol in Tables respectively denotes the following. group. Me ismethyl, Et is ethyl, Pr is propyl, OMe is methoxy, c-C₃ H₅ iscyclopropyl, c-C₅ H₉ is cyclopentyl, c-C₆ H₁₁ is cyclohexyl, i-Bu isisobutyl, t-Bu is tert-butyl and Ph is phenyl.

                                      TABLE 1                                     __________________________________________________________________________     ##STR110##                                                                   compound No.                                                                          R.sup.60                                                                           R.sup.6                                                                          R  R.sup.18              mp. (°C.)                     __________________________________________________________________________    1       H    CH.sub.3                                                                         H                                                                                 ##STR111##           121-122                              2       4-CH.sub.3                                                                         CH.sub.3                                                                         H                                                                                 ##STR112##           140-142                              3       4-OCH.sub.3                                                                        CH.sub.3                                                                         H                                                                                 ##STR113##           124-126                              4       4-Cl CH.sub.3                                                                         H                                                                                 ##STR114##           165-167                              5       3-Cl CH.sub.3                                                                         H                                                                                 ##STR115##           156-158                              6       2-Cl H  H                                                                                 ##STR116##            98-100                              7       2-Cl CH.sub.3                                                                         H                                                                                 ##STR117##           118-122                              8       2-Cl C.sub.2 H.sub.5                                                                  H                                                                                 ##STR118##           115-116                              9       2-Cl CH.sub.3                                                                         CH.sub.3                                                                          ##STR119##           130-131                              10      2-Cl CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR120##           97-99                                11      2-Cl CH.sub.3                                                                         H                                                                                 ##STR121##           122-125                              12      2-Cl CH.sub.3                                                                         H                                                                                 ##STR122##           106-108                              13      2-Cl CH.sub.3                                                                         H  C.sub.4 H.sub.9       107-109                              14      2-Cl CH.sub.3                                                                         H  C.sub.8 H.sub.17      80-82                                __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    (continued from Table 1)                                                      compound                                                                      No.   R.sup.60 R.sup.6                                                                             R    R.sup.18                       mp.                  __________________________________________________________________________                                                             (°C.)         15    2-Cl     CH.sub.3                                                                            H    C.sub.16 H.sub.33               58-60               16    2-Cl     CH.sub.3                                                                            CH.sub.3                                                                           C.sub.6 H.sub.13               108-110              17    2-Cl     CH.sub.3                                                                             ##STR123##                                                                         ##STR124##                    190-191.5                                                                     (p-toluen-                                                                    sulfonate)           18    2-Cl     CH.sub.3                                                                             ##STR125##                                                                         ##STR126##                    190-191.5                                                                     (p-toluen-                                                                    sulfonate)           19    2-Cl     CH.sub.3                                                                            H                                                                                   ##STR127##                    187-189              20    2-Cl     CH.sub.3                                                                            CH.sub.3                                                                            ##STR128##                    162-163              21    2-Cl     CH.sub.3                                                                            H    C.sub.6 H.sub.13               111-113              22    2-CH.sub.3                                                                             CH.sub.3                                                                            H    C.sub.6 H.sub.13               135-137              23    2-OCH.sub.3                                                                            CH.sub.3                                                                            H    C.sub.6 H.sub.13               128-130              24    2-OCH.sub.3                                                                            CH.sub.3                                                                            H    C.sub.8 H.sub.17                76-78               25    2-OCH.sub.3                                                                            CH.sub.3                                                                            H    C.sub.10 H.sub.21               90-92               26    2-CH.sub.3                                                                             CH.sub.3                                                                            H    C.sub.10 H.sub.21               61-63               27    2-Cl     CH.sub.3                                                                            H    C.sub.12 H.sub.25              oily substance       28    2-Cl     CH.sub.3                                                                            H                                                                                   ##STR129##                    134-136              29    2-Cl     CH.sub.3                                                                            H                                                                                   ##STR130##                    112-114              30    2-F      CH.sub.3                                                                            H                                                                                   ##STR131##                    122-124              31    4-OH     CH.sub.3                                                                            H                                                                                   ##STR132##                    240-242              32    4-OC.sub.2 H.sub.4 N(CH.sub.3).sub.2                                                   CH.sub.3                                                                            H                                                                                   ##STR133##                    122-125              33    2-Cl                                                                                    ##STR134##                                                                         CH.sub.3                                                                            ##STR135##                    116-119              __________________________________________________________________________

                                      TABLE 2'                                    __________________________________________________________________________    (continued from Table 1)                                                      compound No.                                                                          R.sup.60                                                                         R.sup.6                                                                          R             R.sup.18            mp. (°C.)              __________________________________________________________________________    34      2-Cl                                                                             t-Bu                                                                             CH.sub.3                                                                                     ##STR136##         125-127                       35      2-Cl                                                                             C.sub.3 H.sub.7                                                                  H                                                                                            ##STR137##          74-77                        36      2-Cl                                                                             CH.sub.3                                                                         H                                                                                            ##STR138##         173-175                       37      2-Cl                                                                             CH.sub.3                                                                         H                                                                                            ##STR139##         171-173                       38      2-Cl                                                                             CH.sub.3                                                                         CH.sub.3                                                                                     ##STR140##         oily substance                39      2-Cl                                                                             CH.sub.3                                                                         CH.sub.3                                                                                     ##STR141##         oily substance                40      2-Cl                                                                             CH.sub.3                                                                         CH.sub.3                                                                                     ##STR142##         183-184                       41      2-Cl                                                                             CH.sub.3                                                                         CH.sub.3                                                                                     ##STR143##         195-196                       42      4-Cl                                                                             CH.sub.3                                                                          ##STR144##                                                                                  ##STR145##         118-120                       43      2-Cl                                                                             CH.sub.3                                                                          ##STR146##                                                                                  ##STR147##         109-111                       44      2-Cl                                                                             CH.sub.3                                                                          ##STR148##                                                                                  ##STR149##         170-172                       45      4-Cl                                                                             CH.sub.3                                                                          ##STR150##                                                                                  ##STR151##         127-128                       46      2-Cl                                                                             CH.sub.3                                                                          ##STR152##                                                                                  ##STR153##         oily substance                47      2-Cl                                                                             CH.sub.3                                                                         H             C.sub.2 H.sub.5     143-146                       48      2-Cl                                                                             CH.sub.3                                                                          ##STR154##   C.sub.2 H.sub.5     284-286 (decomposition)       __________________________________________________________________________

                  TABLE 2"                                                        ______________________________________                                        (continued from Table 1)                                                      com-                                                                          pound                                     mp.                                 No.   R.sup.60                                                                             R.sup.6                                                                              R               R.sup.18                                                                            (°C.)                        ______________________________________                                        49    2-Cl   CH.sub.3                                                                              ##STR155##     C.sub.2 H.sub.5                                                                     259                                 50    2-Cl   CH.sub.3                                                                              ##STR156##     C.sub.2 H.sub.5                                                                     159- 160                            51    2-Cl   CH.sub.3                                                                              ##STR157##     C.sub.2 H.sub.5                                                                     250- 252                            ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________     ##STR158##                                                                                               (R.sup.17, R.sup.18)                              compound No.                                                                          R.sup.60                                                                         R.sup.6                                                                          R             ring formation   mp. (°C.)                 __________________________________________________________________________    52      2-Cl                                                                             CH.sub.3                                                                          ##STR159##                                                                                  ##STR160##      150                              53      2-Cl                                                                             CH.sub.3                                                                         H                                                                                            ##STR161##      136-139                          54      2-Cl                                                                             CH.sub.3                                                                         CH.sub.3                                                                                     ##STR162##      oily substance                   55      2-Cl                                                                             CH.sub.3                                                                         CH.sub.3                                                                                     ##STR163##      126-132                          56      2-Cl                                                                             CH.sub.3                                                                         CH.sub.3                                                                                     ##STR164##      232-238                          57      2-Cl                                                                             CH.sub.3                                                                          ##STR165##                                                                                  ##STR166##      304-306 (decomposition)          __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR167##                                                                   compound No.                                                                          R.sup.60                                                                         Y        R  R.sup.18           mp. (°C.)                    __________________________________________________________________________    58      2-Cl                                                                             H        H                                                                                 ##STR168##        181-183                             59      2-Cl                                                                             H        CH.sub.3                                                                          ##STR169##        185-188                             60      2-Cl                                                                             H        H  C.sub.6 H.sub.13   141-143                             61      2-Cl                                                                             H        CH.sub.3                                                                         C.sub.6 H.sub.13   169-171                             62      2-Cl                                                                              ##STR170##                                                                            H  C.sub.8 H.sub.17   117-118 (difumarate)                63      2-Cl                                                                              ##STR171##                                                                            H  C.sub.6 H.sub.13   154-155 (difumarate)                64      2-Cl                                                                              ##STR172##                                                                            H                                                                                 ##STR173##        181-182.5 (oxalate)                 65      2-Cl                                                                              ##STR174##                                                                            CH.sub.3                                                                          ##STR175##        172-173 (oxalate)                   __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    compound No.                                                                          compound                      mp. (°C.)                        __________________________________________________________________________    66                                                                                     ##STR176##                   131-133                                 67                                                                                     ##STR177##                   124-127                                 68                                                                                     ##STR178##                   218-223                                 69                                                                                     ##STR179##                   227-228                                 70                                                                                     ##STR180##                   164-165                                 71                                                                                     ##STR181##                   257-259                                 __________________________________________________________________________

                  TABLE 6                                                         ______________________________________                                         ##STR182##                                                                   com-                                                                          pound                                                                         No.   R.sup.60                                                                             R.sup.17                                                                             R.sup.18  R.sup.6                                                                             R.sup.61                                                                            mp. (°C.)                    ______________________________________                                        72    4-Cl   H      Et        Me    3-Me  261-264                             73    4-Cl   H      Et        Me    2-Cl  254-258                             74    4-Cl   H      Et        Me    3-Cl  255-258                             75    4-Cl   H      Et        Me    4-Cl  280-281                             76    4-Cl   H      Et        Me    3-OMe 268-270                             77    4-Cl   H      C.sub.6 H.sub.13                                                                        Me    3-Cl  254-255                             78    4-Cl   H      hexyl     Me    3-Me  260-262                             79    3-Cl   H      Et        Me    3-Me  267-270                             80    2-Cl   H      4-i-BuPh(CH.sub.2).sub.2                                                                Me    3-Me  235                                 81    2-Cl   H      Et        Pr    3-Me  262-263                             82    4-Cl   H      octyl     Me    3-Me  231-232                             83    2-Cl   Me     Me        Me    3-Me  241-243                             84    2-Cl   H      Et        cyclo-                                                                              3-Me  259-260                                                           hexyl                                           85    2-Cl   H      Et        Me    3-Me  250-252                             86    4-Me   H      Et        Me    3-Me  267-270                             87    4-Cl   H      Et        Me    H     274-276                             88    H      H      Et        Me    3-Me  272-274                             89    2-Cl   (CH.sub.2).sub.4                                                                             Me    3-Me  241-243                               90    4-Cl   H      Et        Me    2-OMe 250-251                             91    2-Cl   H      Et        Me    3-OMe 269-272                             92    2-Cl   H      Et        Me    2-OMe 271                                 ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                         ##STR183##                                                                   compound                                                                      No.     R.sup.60                                                                             R.sup.17                                                                             R.sup.18                                                                           R.sup.6                                                                             R.sup.61                                                                            Z    mp. (°C.)                  ______________________________________                                        93      2-Cl   H      Et   Me    H     S    212-214                           94      4-Cl   H      Et   Me    4-OMe O    279                               95      2-Cl   H      Et   Me    4-OMe O    260-262                           96      4-Cl   H      Et   Me    4-Br  O    277-278                           97      4-Cl   H      C.sub.4 H.sub.9                                                                    Me    3-OMe O    243-245                           98      4-Cl   H      C.sub.4 H.sub.9                                                                    Me    3-Me  O    259-260                           99      4-Cl   H      C.sub.4 H.sub.9                                                                    Me    2-OMe O    176-178                           100     2-Cl   H      Et   cyclo-                                                                              2-OMe O    269-271                                                      hexyl                                              ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                         ##STR184##                                                                   compound No.                                                                            R.sup.60                                                                             R.sup.17                                                                              R.sup.18                                                                           Y     R.sup.61                                                                            mp. (°C.)                    ______________________________________                                        101       2-Cl   H       Et   Me    4-OMe 201-203                             102       2-Cl   H       Et   Me    4-Cl  241-243                             103       2-Cl   H       Et   Me    2-OMe 224-225                             104       2-Cl   H       Et   Me    H     238-239                             105       2-Cl   H       Et   Me    3-Cl  187-189                             106       2-Cl   H       Et   Me    2-OMe 164-166                             107       2-Cl   H       Et   Me    4-Me  228-229                             108       2-Cl   H       Et   Me    4-Br  229-231                             109       2-Cl   H       Et   Me    2-Me  166-167.5                           110       2-Cl   H       Et   Me    2-Cl  173-175                             111       2-Cl   H       Et   Me    3-Me  226-227                             ______________________________________                                    

                                      TABLE 9                                     __________________________________________________________________________    compound No.                                                                          compound                      mp. (°C.)                        __________________________________________________________________________    112                                                                                    ##STR185##                   176-178                                 113                                                                                    ##STR186##                   212-214                                 114                                                                                    ##STR187##                   196-199                                 __________________________________________________________________________

                  TABLE 10                                                        ______________________________________                                         ##STR188##                                                                   com-                                                                          pound                                       mp.                               No.   R.sup.17                                                                             R.sup.18                                                                             R.sup.6                                                                             R.sup.12    Ar    (°C.)                      ______________________________________                                        201   H      Et     c-C.sub.6 H.sub.11                                                                   ##STR189## 2-ClPh                                                                              268- 269                          202   H      Et     c-C.sub.6 H.sub.11                                                                   ##STR190## 2-ClPh                                                                              260                               203   H      Et     c-C.sub.6 H.sub.11                                                                   ##STR191## 2-ClPh                                                                              265- 266                          204   H      Et     c-C.sub.5 H.sub.9                                                                    ##STR192## 2-ClPh                                                                              246- 247                          205   H      Et     c-C.sub.5 H.sub.9                                                                    ##STR193## 2-ClPh                                                                              250- 254                          206   H      Et     c-C.sub.3 H.sub.5                                                                    ##STR194## 2-ClPh                                                                              249- 251                          207   H      Et     c-C.sub.3 H.sub.5                                                                    ##STR195## 2-ClPh                                                                              270- 272                          208   H      Et     c-C.sub.3 H.sub.5                                                                    ##STR196## 2-ClPh                                                                              252- 253                          209   H      Et     c-C.sub.5 H.sub.9                                                                    ##STR197## 2-ClPh                                                                              270- 272                          210   H      Et     c-C.sub.3 H.sub.5                                                                    ##STR198## 2-ClPh                                                                              273- 276                          211   H      Et     c-C.sub.6 H.sub.11                                                                   ##STR199## 2-ClPh                                                                              262- 263                          212   H      Et     c-C.sub.6 H.sub.11                                                                   ##STR200## 2-ClPh                                                                              232- 235                          213   H      Et     Ph                                                                                   ##STR201## 2-ClPh                                                                              268- 270                          214   H      Et     c-C.sub.6 H.sub.11                                                                   ##STR202## 2-ClPh                                                                              268- 269                          ______________________________________                                    

                                      TABLE 11                                    __________________________________________________________________________    (continued from Table 10)                                                     compound No.                                                                          R.sup.17                                                                         R.sup.18                                                                         R.sup.6                                                                              R.sup.12  Ar  mp. (°C.)                           __________________________________________________________________________    215     H  Et c-C.sub.6 H.sub.11                                                                    ##STR203##                                                                             2-ClPh                                                                            251-253                                    216     H  Et c-C.sub.6 H.sub.11                                                                    ##STR204##                                                                             2-ClPh                                                                            233-236                                    217     H  Et Ph                                                                                    ##STR205##                                                                             2-ClPh                                                                            249-253                                    218     H  Et c-C.sub.6 H.sub.11                                                                    ##STR206##                                                                             2-ClPh                                                                            257-260                                    219     H  Et (CH.sub.3).sub.2 CH                                                                   ##STR207##                                                                             2-ClPh                                                                            279                                        220     H  Et butyl                                                                                 ##STR208##                                                                             2-ClPh                                                                            260-261                                    221     H  Et butyl                                                                                 ##STR209##                                                                             2-ClPh                                                                            247-250                                    222     H  Et Me                                                                                    ##STR210##                                                                             2-ClPh                                                                            272-273                                    223     H  Et Me                                                                                    ##STR211##                                                                             2-ClPh                                                                            254-255                                    224     H  Et Me                                                                                    ##STR212##                                                                             2-ClPh                                                                            267-270                                    225     H  Et Me                                                                                    ##STR213##                                                                             2-ClPh                                                                            274-275                                    226     H  Et Me                                                                                    ##STR214##                                                                             2-ClPh                                                                            272-274                                    227     H  Et tert-butyl                                                                            ##STR215##                                                                             2-ClPh                                                                            278-279                                    228     H  Et Et                                                                                    ##STR216##                                                                             2-ClPh                                                                            270-272                                    229     H  Et Me                                                                                    ##STR217##                                                                             2-ClPh                                                                            273-276                                    230     H  Et tert-butyl                                                                            ##STR218##                                                                             2-ClPh                                                                            232-234                                    __________________________________________________________________________

                                      TABLE 11'                                   __________________________________________________________________________    (continued from Table 10)                                                     compound No.                                                                          R.sup.17                                                                         R.sup.18                                                                         R.sup.6                                                                              R.sup.12   Ar  mp. (°C.)                          __________________________________________________________________________    231     H  Et (CH.sub.3).sub.2 CH                                                                   ##STR219##                                                                              2-ClPh                                                                            266-267                                   232     H  Et Et                                                                                    ##STR220##                                                                              2-ClPh                                                                            260-262                                   233     H  Et Et                                                                                    ##STR221##                                                                              2-ClPh                                                                            254-256                                   234     H  Et Pr                                                                                    ##STR222##                                                                              2-ClPh                                                                            269-270                                   235     H  Et (CH.sub.3).sub.2 CH                                                                   ##STR223##                                                                              2-ClPh                                                                            250-252                                   236     H  Et butyl                                                                                 ##STR224##                                                                              2-ClPh                                                                            229-231                                   237     H  Et (CH.sub.3).sub.2 CH                                                                   ##STR225##                                                                              2-ClPh                                                                            254-255                                   238     H  Et tert-butyl                                                                            ##STR226##                                                                              2-ClPh                                                                            251-254                                   239     H  Et butyl                                                                                 ##STR227##                                                                              2-ClPh                                                                            251-253                                   240     H  Et Et                                                                                    ##STR228##                                                                              2-ClPh                                                                            262-263                                   241     H  Me Me                                                                                    ##STR229##                                                                              2-ClPh                                                                            255-257                                   242     H  Et Pr                                                                                    ##STR230##                                                                              2-ClPh                                                                            260-263                                   243     H  Et heptyl                                                                                ##STR231##                                                                              2-ClPh                                                                            235-237                                   244     H  Et Me                                                                                    ##STR232##                                                                              4-ClPh                                                                            268-269                                   245     H  Et Me                                                                                    ##STR233##                                                                              4-ClPh                                                                            242-244                                   246     H  Et Me                                                                                    ##STR234##                                                                              2-ClPh                                                                            272-274 (decomposition)                   __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________     ##STR235##                                                                   compound No.                                                                          R.sup.60                                                                          R.sup.6                                                                          R                R.sup.18          mp. (°C.)            __________________________________________________________________________    247     4-Cl                                                                              Me CH.sub.2 COOH    Et                198-202                     248     4-Cl                                                                              Me                                                                                ##STR236##      Et                247-248                     249     4-Cl                                                                              Me                                                                                ##STR237##      Et                217-218                     250     4-Cl                                                                              Me                                                                                ##STR238##      Et                198-200                     251     4-Cl                                                                              Me                                                                                ##STR239##      Et                238-239                     252     4-Cl                                                                              Me                                                                                ##STR240##      Et                244                         253     2-Cl                                                                              Me                                                                                ##STR241##                                                                                     ##STR242##       158-162                     254     4-Cl                                                                              Me                                                                                ##STR243##      Et                239-242                     255     2-Cl                                                                              Me                                                                                ##STR244##      Et                244                         256     2-Cl                                                                              Me                                                                                ##STR245##      Et                158-159                     257     4-OMe                                                                             Me                                                                                ##STR246##      Et                190-192                     __________________________________________________________________________

                  TABLE 13                                                        ______________________________________                                         ##STR247##                                                                   com-                                                                          pound                                     mp.                                 No.   R.sup.60                                                                             Y      R                R.sup.18                                                                           (°C.)                        ______________________________________                                        258   2-Cl   Me                                                                                    ##STR248##      Et   181- 182.5                          259   2-Cl   Me     CH.sub.2 COOH    Et   228- 231                            ______________________________________                                    

                                      TABLE 14                                    __________________________________________________________________________     ##STR249##                                                                   compound No.                                                                          R.sup.60  R.sup.6    R.sup.18 R.sup.17                                                                         mp. (°C.)                     __________________________________________________________________________    301     4-OCH.sub.3                                                                             C.sub.11 H.sub.23                                                                        Et       H   91-93                               302     4-OH      C.sub.11 H.sub.23                                                                        Et       H   96-98                               303     4-CH.sub.3                                                                              C.sub.17 H.sub.35                                                                        Et       H   83-84                               304     H         C.sub.11 H.sub.23                                                                        Et       H  oily substance                       305     H         PhO(CH.sub.2).sub.2                                                                      Et       H   75-78                               306     2-Cl      C.sub.9 H.sub.19                                                                         (CH.sub.2).sub.4                                                                          111-113                              307     2-Cl      C.sub.11 H.sub.23                                                                        (CH.sub.2).sub.4                                                                           65-67                               308     2-Cl      C.sub.15 H.sub.31                                                                        (CH.sub.2).sub.4                                                                           76-78                               309     2-Cl      C.sub.17 H.sub.35                                                                        (CH.sub.2).sub.4                                                                           73-74                               310     2-Cl      C.sub.9 H.sub.19                                                                         CH.sub.3 CH.sub.3                                                                          83-84                               311     2-Cl      C.sub.11 H.sub.23                                                                        CH.sub.3 CH.sub.3                                                                          93-95                               312     2-Cl      C.sub.15 H.sub.31                                                                        CH.sub.3 CH.sub.3                                                                          63-65                               313     2-Cl      C.sub.17 H.sub.35                                                                        CH.sub.3 CH.sub.3                                                                          93-95(HCl)                          314     2-Cl      4-i-BuPh(CH.sub.2).sub.3                                                                 CH.sub.3 CH.sub.3                                                                         115-117                              315     2-Cl      C.sub.9 H.sub.19                                                                         Et       H  113-114(HCl)                         316     2-Cl      C.sub.11 H.sub.23                                                                        Et       H   88-89(HCl, 1/4H.sub.2 O)            317     2-Cl      C.sub.15 H.sub.31                                                                        Et       H  119-121(HCl)                         318     2-Cl      C.sub.17 H.sub.35                                                                        Et       H  116-119(HCl)                         319     2-Cl      PhO(CH.sub.2).sub.2                                                                      Et       H  126-128                              320     3-Cl      PhO(CH.sub.2).sub.2                                                                      Et       H   90-92                               321     3-Cl      C.sub.9 H.sub.19                                                                         Et       H   86-87                               322     3-Cl      C.sub.11 H.sub.23                                                                        Et       H   74-76                               323     3-Cl      C.sub.15 H.sub.31                                                                        Et       H   76-77                               324     2-Cl      CH.sub.3   4-i-BuPh(CH.sub.2).sub.2                                                               H   85-87                               325     4-Cl      PhO(CH.sub.2).sub.2                                                                      Et       H  128-130                              326     4-Cl      C.sub.9 H.sub.19                                                                         Et       H  130-131( 1/2H.sub.2 O)               327     4-Cl      C.sub.11 H.sub.23                                                                        Et       H  107-108                              328     4-Cl      C.sub.15 H.sub.31                                                                        Et       H  115-117                              329     4-Cl      C.sub.17 H.sub.35                                                                        Et       H  108-109(H.sub.2 O)                   330     4-Cl      4-i-BuPh(CH.sub.2).sub.3                                                                 Et       H  108-109                              331     4-Cl      CH.sub.2 NHCOC.sub.11 H.sub.23                                                           Et       H   98-99                               332     4-Cl      C.sub.11 H.sub.23                                                                        (CH.sub.2).sub.4                                                                          158-160(HCl)                         333     4-Cl      C.sub.15 H.sub.31                                                                        (CH.sub.2).sub.4                                                                          121-123(HCl)                         334     4-Cl      C.sub.11 H.sub.23                                                                        C.sub.8 H.sub.17                                                                       H   78-81                               335     4-Cl      C.sub.15 H.sub.31                                                                        C.sub.8 H.sub.17                                                                       H   68-69                               336     4-Cl      C.sub.17 H.sub.35                                                                        C.sub.8 H.sub.17                                                                       H   65-66                               337     4-Cl      CH.sub.3   C.sub.16 H.sub.33                                                                      H   71-73                               338     4-Cl      C.sub.4 H.sub.9                                                                          C.sub.16 H.sub.33                                                                      H  135-137(HCl)                         339     4-Cl      C.sub.9 H.sub.19                                                                         C.sub.16 H.sub.33                                                                      H   69-70                               340     4-Cl      C.sub.11 H.sub.23                                                                        C.sub.16 H.sub.33                                                                      H   60-62                               341     4-Cl      C.sub.15 H.sub.31                                                                        C.sub.16 H.sub.33                                                                      H   83-85                               342     4-Cl      C.sub.17 H.sub.35                                                                        C.sub.16 H.sub.33                                                                      H   90-92                               343     2-OCH.sub.3                                                                             PhO(CH.sub.2).sub.2                                                                      Et       H  120-121                              344     2-OCH.sub.3                                                                             C.sub.11 H.sub.23                                                                        Et       H   55-56                               345     4-OCH.sub.3                                                                             PhO(CH.sub.2).sub.2                                                                      Et       H  111-113                              346     4-OCH.sub.3                                                                             C.sub.4 H.sub.9                                                                          Et       H  101-103                              347     4-OCH.sub.3                                                                             C.sub.5 H.sub.11                                                                         Et       H  113-115                              348     4-OCH.sub.3                                                                             C.sub.7 H.sub.15                                                                         Et       H  106-108                              349     4-OCH.sub.3                                                                             C.sub.9 H.sub.19                                                                         Et       H  106-108                              350     4-OCH.sub.3                                                                             C.sub.15 H.sub.31                                                                        Et       H   93-95                               351     4-OCH.sub.3                                                                             C.sub.17 H.sub.35                                                                        Et       H   85-87                               352     4-OCH.sub.3                                                                             C.sub.11 H.sub.23                                                                        C.sub.8 H.sub.17                                                                       H   57-58                               353     4-OCH.sub.3                                                                             C.sub.15 H.sub.31                                                                        C.sub.8 H.sub.17                                                                       H   66-67( 1/2H.sub.2 O)                354     4-Me.sub.2 N(CH.sub.2).sub.2 O                                                          C.sub.11 H.sub.23                                                                        Et       H   79-80( 1/4H.sub.2 O)                355     2-CH.sub.3                                                                              CH.sub.3   C.sub.6 H.sub.13                                                                       H  oily substance                       356     2-CH.sub.3                                                                              PhO(CH.sub.2).sub.2                                                                      Et       H  133-135                              357     4-CH.sub.3                                                                              C.sub.11 H.sub.23                                                                        Et       H   77-78                               358     4-CH.sub.3                                                                              C.sub.15 H.sub.31                                                                        Et       H   69-70                               359     4-CH.sub.3                                                                              C.sub.11 H.sub.23                                                                        C.sub.8 H.sub.17                                                                       H   71-73                               360     4-OCH.sub.3                                                                             C.sub.4 H.sub.9                                                                          C.sub.16 H.sub.33                                                                      H   56-57                               361     4-OCH.sub.3                                                                             C.sub.11 H.sub.23                                                                        C.sub.16 H.sub.33                                                                      H   56-58                               362     4-OCH.sub.3                                                                             C.sub.7 H.sub.35                                                                         C.sub.16 H.sub.33                                                                      H   79-81                               363     4-Cl      C.sub.11 H.sub.23                                                                        Me       Me  87-89                               364     4-Cl      4-i-BuPhCH.sub.2                                                                         Me       Me 141-143                              365     4-Cl      4-i-BuPh(CH.sub.3).sub.3                                                                 Me       Me 146-148                              366     4-Cl      4-i-BuPh(CH.sub.2).sub.4                                                                 Me       Me  87-89                               367     4-Cl      4-i-BuPh(CH.sub.2).sub.5                                                                 Me       Me 102-103                              __________________________________________________________________________

                  TABLE 15                                                        ______________________________________                                         ##STR250##                                                                   compound No.                                                                              R.sup.60 R.sup.6  R.sup.15                                                                             mp. (°C.)                         ______________________________________                                        368         2-Cl     C.sub.11 H.sub.23                                                                      Cl     124-125                                  369         2-Cl     C.sub.15 H.sub.31                                                                      Cl      95-96                                   370         H        C.sub.11 H.sub.23                                                                      H       83-84                                   ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                        compound No.                                                                            compound              mp. (°C.)                              ______________________________________                                        371                                                                                      ##STR251##           112-114                                       ______________________________________                                    

    TABLE 17      -      ##STR252##      No. Ar      ##STR253##      R R' R.sup.6 R.sup.15 R.sup.16 mp. (°C.)      68     ##STR254##      N H H CH.sub.3 Cl H 218-223      69 Ph N H H CH.sub.3 Cl H 227-228     501      ##STR255##      N      ##STR256##      CO.sub.2 C.sub.2      H.sub.5 CH.sub.3 H H 168-172                      502      ##STR257##      N      ##STR258##      H CH.sub.3 H H 281-285     503      ##STR259##      N      ##STR260##      H CH.sub.3 H H 270-273     504      ##STR261##      N NHCO.sub.2 CH.sub.2      Ph H CH.sub.3 H H 212-215                           505      ##STR262##      N      ##STR263##      H CH.sub.3 H H 198-201     506      ##STR264##      N      ##STR265##      H CH.sub.3 H H 271-273(decomp.)     507      ##STR266##      N NHSO.sub.2 CH.sub.2      Ph H CH.sub.3 H H 142-157(amorphous)                           508      ##STR267##      N      ##STR268##      H CH.sub.3 H H 275-279     509 Ph N      ##STR269##      H CH.sub.3 H H 109-113(amorphous)     510 Ph N      ##STR270##      H CH.sub.3 H H 123-126     511 Ph N CH.sub.2 OCOCH.sub.2 Ph H CH.sub.3 H H  61-67(amorphous)                                                                       512      ##STR271##      N H H n-C.sub.7      H.sub.15 H H 151-153                     513      ##STR272##      N H H n-C.sub.11 H.sub.23 H H      97-98                                    514      ##STR273##      N H H n-C.sub.15 H.sub.31 H H      95-97                                    515      ##STR274##      NH H H n-C.sub.11 H.sub.23 H H      94-95                                     516      ##STR275##      O H H n-C.sub.11 H.sub.23 H H      87-89                                    517      ##STR276##      N H H      ##STR277##      H H      63-65         518 Ph N      ##STR278##      H CH.sub.3 H H 100-104(amorphous)     519 Ph N CH.sub.3 H CH.sub.3 n-C.sub.10 H.sub.21 H oily substance             520 Ph N CH.sub.3 H CH.sub.3 H n-C.sub.10 H.sub.21 111-112                                                                        521      ##STR279##      N      ##STR280##      H CH.sub.3 H H 263-265     522      ##STR281##      N      ##STR282##      H CH.sub.3 H H 274-278     523      ##STR283##      N      ##STR284##      H CH.sub.3 H H 272-274     524      ##STR285##      N CONHNHCOPh H CH.sub.3 H H 243-245     525      ##STR286##      N NHCONHCOPh H CH.sub.3 H H 231-233     526      ##STR287##      N      ##STR288##      H CH.sub.3 H H 212-214     527      ##STR289##      N CONHNHPh H CH.sub.3 H H 175-177     528      ##STR290##      N CONHOCH.sub.2      Ph H CH.sub.3 H H 138-139                     529      ##STR291##      N CONHCH.sub.2      Ph H CH.sub.3 H H 265-267                    530      ##STR292##      N NHCOCONHPh H CH.sub.3 H H 247-248      531      ##STR293##      N      ##STR294##      CH.sub.3 H H 269-271      532 Ph N      ##STR295##      H CH.sub.3 Cl H 270-274     533 Ph N      ##STR296##      H CH.sub.3 Cl H 158-161     534 Ph N CH.sub.2      OC(CH.sub.3).sub.3 H CH.sub.3 H H 202-206                      535      ##STR297##      N NHCONHCH.sub.2      Ph H CH.sub.3 H H 270-273                      536      ##STR298##      N      ##STR299##      H CH.sub.3 H H 257-259     537      ##STR300##      N      ##STR301##      H CH.sub.3 H H 287-290     538      ##STR302##      N      ##STR303##      H CH.sub.3 H H 285-287     539      ##STR304##      N      ##STR305##      H CH.sub.3 H H 196-200     540      ##STR306##      N      ##STR307##      H CH.sub.3 H H 133-137

                  TABLE 18                                                        ______________________________________                                         ##STR308##                                                                   compound No.   R.sup.18  X       mp. (°C.)                             ______________________________________                                        601            H         O       186-188                                      602            Et        O       181-183                                      603            H         S       178-179                                      604            Et        S                                                    605            Br        S                                                    ______________________________________                                    

                  TABLE 19                                                        ______________________________________                                         ##STR309##                                                                   compound No.   R.sup.18 R.sup.6   mp. (°C.)                            ______________________________________                                        606            H        Me        212                                         607            Et       Me        159-161                                     608            Br       Me                                                    ______________________________________                                    

The method for determining the bone resorption-inhibitory activity ofthe Compound (I) and the results are shown in the following.

Bone resorption-inhibitory activity

The determination of the bone resorption-inhibitory activity basicallyfollowed the method of Raisz [J. Clin. Invest., vol. 44, pp. 103-116(1965)].

A 1-2 days old new born ICR mouse was intraperitoneally administeredwith 1.5μ Ci ⁴⁵ Ca (CaCl₂ solution of isotope of calcium) and parietalbone was asceptically removed the next day. The parietal bone was splitinto two along the central sature line and one of them was used as acontrol and the other was used for the experiment. The bone waspreincubated in 0.5 ml of a BGJb medium (Fitton-Jackson modification,GIBCO Laboratories, U.S.A.) added with the test compound to aconcentration of 5 μM or 20 μM and bovine serum albumin (1 mg/ml) at 37°C. for 2 days, and further incubated in the aforementioned mediumcontaining 50 nM hPTH (1-34) for 3 days. After the incubation, theradioactivity of ⁴⁵ Ca in the medium and in the bone was measured andthe ratio (%) of ⁴⁵ Ca released from the bone into the medium wascalculated. ##EQU1##

Using the bone obtained from the same mouse and treated in the samemanner without the test compound as a control, the ratio (%) against thecontrol was calculated according to the following equation. ##EQU2##

The average of these values obtained from four pairs from each group wascalculated. The results are shown in Tables 20 and 21.

                  TABLE 20                                                        ______________________________________                                                                  bone resorption-                                    compound   concentration  inhibitory action,                                  No.        (μM)        % against control                                   ______________________________________                                         1         20             30.7                                                 5         "              26.7                                                 6         "              30.2                                                 9         "              23.7 (7.5)                                          11         "              23.4                                                19         "              61.7                                                22         "              23.4                                                25         "              17.5                                                27         "              17.0                                                28         "              16.5                                                29         "              16.4                                                30         "              20.6                                                31         "              26.4                                                32         "              16.0                                                34         "              15.5                                                35         "              20.0                                                36         "              21.9                                                38         "              46.0                                                40         "              32.8                                                42         "              16.9                                                43         "              21.2                                                44         "              15.7                                                46         "              21.1                                                48         "              25.7                                                49         "              22.3                                                50         "              26.4                                                51         "              26.9                                                52         "              29.9                                                53         "              73.5                                                54         "              31.7                                                60         "              58.6                                                62         "              27.4                                                64         20             25.2                                                66         "              56.3                                                67         "              55.3                                                68         "              57.5                                                69         "              21.9                                                70         "              50.3                                                75          5             47.7                                                76         "              29.5                                                78         "              45.4                                                83         "              35.0                                                84         "              65.3                                                86         "              30.3                                                87         "              31.6                                                88         "              33.8                                                90         "              34.2 (0.25)                                         93         "              63.5                                                98         "              35.0                                                100        "              55.5                                                112        "              54.8                                                250        20             27.3                                                254        "              32.5                                                255        "              54.3                                                257        "              27.1                                                302        "              22.4                                                304        "              28.6                                                307        "              42.4                                                324        "              33.1                                                330        "              35.6                                                348        "              30.3                                                354        "              23.2                                                357        "              24.7                                                ______________________________________                                         Note:                                                                         The figures in parentheses show IC.sub.50 (μM).                       

                  TABLE 21                                                        ______________________________________                                                                  bone resorption-                                    compound   concentration  inhibitory action,                                  No.        (μM)        % against control                                   ______________________________________                                        501        20             29.5                                                502        "              31.8                                                503        "              30.4                                                504        "              24.6                                                505        "              53.5                                                506        "              32.5                                                507        "              35.6                                                508        "              48.1                                                509        "              35.0                                                510        "              28.3                                                511        "              37.7                                                513        "              43.3                                                515        "              29.9                                                516        20             22.4                                                517        "              47.3                                                518        "              45.4                                                519        "              21.1                                                520        "              22.5                                                521        "              29.6                                                522        "              32.8                                                523        "              26.7                                                525        "              26.8                                                530        "              28.2                                                531        "              34.4                                                532        "              28.1 (0.93                                          ______________________________________                                         Note:                                                                         The figures in parentheses show IC.sub.50 (μM).                       

The acute toxicity of the compounds of the present invention wasexamined using 6 male mice. The test compound was orally administeredand the mice were observed for 5 days. As a result, no death case wasfound at the dose of 1000 mg/kg.

As demonstrated in the above, the compounds of the formula (I) of thepresent invention have superior bone resorption-inhibitory activity andare low toxic. It is evident from the results of the aforementioned boneresorption-inhibitory action test that these compounds have an action toreduce the increased amount of calcium in blood serum, which is causedby bone resorption. Accordingly, these compounds are usable aspharmaceutical agents to effectively inhibit bone resorption, to preventdecrease of bone mass and to prevent or suppress the increase of calciumamount in blood serum which is caused by the progress of boneresorption, with regard to Paget's disease, hypercalcemia, osteoporosisand so on in which the progress of bone resorption is considered to bedeeply associated with the symptom, and to the symptoms of progressingbone resorption (development into osteoporosis) along with inflammatoryjoint diseases such as rheumatoid arthritis.

The compounds of the formula (I) and pharmaceutically acceptable saltsthereof of the present invention are used as they are or aspharmaceutical compositions admixed with carrier, excipient and so onknown per se such as lactose, starch, sucrose and magnesium stearate.The administration route may be oral or parenteral. The composition fororal administration may be solid or liquid. Specific examples includetablets, pills, granules, powders, capsules, syrups, emulsions andsuspensions. Examples of the composition for parenteral administrationinclude injections, suppositories, inhalations and percutaneous agentsand the injections may be subcutaneous injections, intradermalinjections or intramuscular injections. Such injections are prepared bya method known per se, by suspending or emulsifying the compound in asterile aqueous solution such as physiological saline or isotonicsolution or oily solution such as sesami oil or soy bean oil. Wherenecessary, a suitable suspending agent such as sodiumcarboxymethylcellulose or non-ionic surfactant, a solubilizer such asbenzyl benzoate or benzyl alcohol, or the like may be added. While thedose varies depending on administration targets, administration route,symptom etc., it is generally 0.1-500 mg, preferably 0.1-100 mg dailyfor an adult.

The present invention is hereinbelow described in datail by way ofexamples and pharmaceutical examples. It should be understood that thepresent invention is not limited to these examples.

EXAMPLE 1

2-Amino-5-(2-(4-isobutylphenyl)ethyl)-3-(2-chlorobenzoyl)thiophene (4.7g) was dissolved in chloroform (100 ml) and D,L-N-phthalylphenylalanylchloride (4.7 g) was added thereto with stirring. The mixture wasrefluxed under heating for 10 hours. After cooling, the reaction mixturewas washed with 5% aqueous solution of sodium hydrogencarbonate andwater, and dried over anhydrous magnesium sulfate. The mixture wasfiltered and concentrated under reduced pressure. After the residue waspurified by silica gel column chromatography, the objective fraction wasconcentrated under reduced pressure to give 4.2 g of2-(N-phthalylphenylalanyl)amino-5-(2-(4-isobutylphenyl)ethyl)-3-(2-chlorobenzoyl)thiopheneas an oily substance.

The compound (4.1 g) obtained as above was dissolved in methanol (50 ml)and hydrazine hydrate (0.9 g) was added thereto with stirring. Themixture was stirred at room temperature for 4 hours. Conc. hydrochloricacid (3 ml) was added thereto and the mixture was heated and stirred at60° C. for 3 hours. The mixture was concentrated under reduced pressure.The residue was dissolved in chloroform (200 ml), washed with 5% sodiumhydrogencarbonate and water, and dried over anhydrous magnesium sulfate.After filtration, the mixture was concentrated under reduced pressure.The obtained oily substance was dissolved in isopropyl alcohol (100 ml)and acetic acid (1.8 g) was added thereto. The mixture was heated andstirred at 75° C. for 20 hours. The reaction mixture was concentratedunder reduced pressure. The residue was dissolved in chloroform, washedwith 5% aqueous solution of sodium hydrogencarbonate and water, anddried over anhydrous magnesium sulfate. After filtration, the mixturewas concentrated under reduced pressure and the residue was purified bysilica gel column chromatography. The objective fraction wasconcentrated under reduced pressure to give 1.75 g of5-(2-chlorophenyl)-7-(2-(4-isobutylphenyl)ethyl)1,3-dihydro-3-benzyl-2H-thieno[2,3-e][1,4]diazepin-2-oneas an amorphous powder.

The compound (0.8 g) obtained as above was dissolved in chloroform (40ml) and phosphorus pentasulfide (0.67 g) was added thereto withstirring. The mixture was refluxed under heating for 4 hours. Aftercooling, the mixture was washed with 5% sodium hydrogencarbonate andwater, and dried over anhydrous magnesium sulfate. After filtration, themixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (40 ml). Hydrazine hydrate (0.2 g) wasadded thereto with stirring and the mixture was stirred for 1 hour. Thereaction mixture was concentrated under reduced pressure and toluene (30ml) was added to the residue. The mixture was dried over anhydrousmagnesium sulfate and filtered. Ethyl orthoacetate (0.8 g) was added tothe filtrate with stirring and the mixture was stirred while heating at75° C. for 2 hours. The reaction mixture was concentrated under reducedpressure and the obtained oily substance was purified by silica gelcolumn chromatography. The objective fraction was concentrated underreduced pressure to give 0.4 g of4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6-benzyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineas an amorphous powder.

EXAMPLE 2

2-Amino-5-(2-(4-isobutylphenyl)ethyl)-3-(2-chlorobenzoyl)thiophene (6.0g) was dissolved in chloroform (100 ml) and D,L-N-phthalylphenylglycylchloride (6.2 g) was added thereto with stirring. The mixture wasrefluxed under heating for 5 hours. After cooling, the reaction mixturewas washed with 5% aqueous sodium hydrogencarbonate and water, and driedover anhydrous magnesium sulfate. The mixture was filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography and the objective fraction was concentratedunder reduced pressure to give 6.3 g of2-(N-phthalylphenylglycyl)amino-5-(2-(4-isobutylphenyl)ethyl)-3-(2-chlorobenzoyl)thiopheneas an oily substance.

Said compound (5.0 g) was dissolved in tetrahydrofuran (60 ml) andhydrazine hydrate (1.0 g) was added thereto with stirring and themixture was stirred for 2 hours. Conc. hydrochloric acid (3 ml) wasadded thereto and the mixture was stirred while heating at 60° C. for 1hour. The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in chloroform (200 ml), washed with 5% aqueoussodium hydrogencarbonate and water, and dried over anhydrous magnesiumsulfate. After filtration, the residue was dissolved in isopropylalcohol (120 ml). Acetic acid (2.3 g) was added thereto and the mixturewas stirred while heating at 70°-75° C. for 40 hours. After cooling, thereaction mixture was concentrated under reduced pressure. The oilysubstance obtained was dissolved in chloroform (300 ml), washed with 5%aqueous sodium hydrogencarbonate and water, and dried over anhydrousmagnesium sulfate. After filtration, the oily substance obtained waspurified by silica gel column chromatography. The objective fraction wasconcentrated under reduced pressure and the residue was crystallizedfrom isopropyl ether to give 0.4 g of5-(2-chlorophenyl)-7-(2-(4-isobutylphenyl)ethyl)-1,3-dihydro-3-phenyl-2H-thieno[2,3-e][1,4]diazepin-2-oneas colorless crystals, melting point 201°-203° C.

The aforementioned compound (0.35 g) was dissolved in chloroform (30 ml)and phosphorus pentasulfide (0.3 g) was added thereto with stirring. Themixture was refluxed under heating for 6.5 hours. After cooling, thereaction mixture was washed with water and 5% sodium hydrogencarbonate,and dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 ml). Hydrazine hydrate (0.2 g) wasadded thereto with stirring and the mixture was stirred for 1 hour. Thereaction mixture was concentrated under reduced pressure and the residuewas dissolved in toluene (20 ml). The mixture was dried over anhydrousmagnesium sulfate and filtered. Ethyl orthoacetate (0.4 g) was addedthereto with stirring and the mixture was stirred while heating at 80°C. for 2 hours. After cooling, the reaction mixture was concentrated andthe oily substance obtained was purified by silica gel columnchromatography. The objective fraction was concentrated under reducedpressure and the residue was crystallized from a mixture of isopropylether-n-hexane to give 0.12 g of4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6-phenyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineas colorless crystals, melting point 170°-172° C.

EXAMPLE 3

7-n-Octyl-5-(2-chlorophenyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-2-one(3.68 g) was dissolved in dry dimethylformamide (30 ml). In an ice bath,sodium hydride (60%, 0.5 g) and then dimethylaminoethyl chloride (1.3 g)were added thereto and the mixture was stirred at room temperature for25 hours. The reaction mixture was poured into water (100 ml), extractedwith ethyl acetate, and an organic layer was dried over anhydrousmagnesium sulfate. After filtration, the oily substance obtained byconcentration under reduced pressure was purified by silica gel columnchromatography. The objective fraction was concentrated under reducedpressure and the residue (3.55 g) was dissolved in ethyl acetate (20ml). A solution of fumaric acid (1.9 g) in ethanol (20 ml) was addedthereto, and the mixture was allowed to stand. The obtained crystalswere recrystallized from isopropyl alcohol to give 2.0 g of7-n-octyl-5-(2-chlorophenyl)-1-(2-dimethylaminoethyl)1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-onedifumarate as white crystals, melting point 117°-118° C.

Preparation of Starting Material 1

5-(2-Chlorophenyl)-7-ethyl1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one(40 g) was dissolved in chloroform (600 ml) and phosphorus pentasulfide(117 g) was added thereto with stirring. The mixture was refluxed for 3hours. After the reaction, the reaction mixture was neutralized withsaturated aqueous sodium bicarbonate, washed with water, and dried overanhydrous magnesium sulfate. The solvent was distilled away underreduced pressure and precipitated crystals were collected by filtrationwith diisopropyl ether and recrystallized from ethanol-chloroform togive 42 g of5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]1,4-diazepine-2-thionehaving a melting point of 198°-199° C. The thione compound obtained (42g) was suspended in methanol (300 ml) and 100% hydrazine hydrate (19 ml)was added thereto under cooling. The mixture was stirred at roomtemperature for 2 hours. After the reaction, the precipitated crystalswere collected by filtration and recrystallized fromethanol-dimethylformamide to give 34 g of5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e]1,4-diazepine-2-hydrazine,melting point 214°-216° C. The hydrazone compound (20 g) was dissolvedin chloroform (200 ml) and cyclohexylcarbonyl chloride (10 g) was addedthereto with stirring. The mixture was stirred at room temperature for 1hour. After the reaction, the reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate and water, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue obtained was dissolved in toluene (200 ml) and acetic acid(5.4 ml) was added thereto. The mixture was refluxed for 3 hours. Afterthe completion of the reaction, the reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate and water, and driedover anhydrous magnesium sulfate. The mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography. The objective fraction was concentrated under reducedpressure to give 15 g of4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,melting point 116°-119° C.

Preparation of Starting Material-2

4-(2-Chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(3.4 g) and sodium hydride (0.56 g) were added to diethyl carbonate (50ml) and the mixture was heated. After refluxing for 1 hour, the reactionmixture was cooled to 20° C., and O-(2,4-dinitrophenyl)-hydroxylamine(2.1 g) was added thereto. The mixture was stirred for 2 hours. Afterthe reaction, the reaction mixture was poured into ice water, and thediethyl carbonate layer was separated. The diethyl carbonate layer waswashed twice with water, and dried over anhydrous magnesium sulfate.Diisopropyl ether was added to the residue obtained by distilling awaydiethyl carbonate under reduced pressure. The precipitated crystals werecollected by filtration and recrystallized from ethyl acetate to give2.1 g ofethyl(6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylatehaving a melting point of 140°-145° C.Ethyl(6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylate(1.8 g) was dissolved in a mixture of ethanol (60 ml) and water (20 ml)and barium hydroxide 8 hydrate (1.14 g) was added thereto. The mixturewas stirred at room temperature for 24 hours. The solvent was distilledaway under reduced pressure and water (50 ml) was added thereto. Themixture was adjusted to pH 2 with 1N hydrochloric acid and stirred for 1hour. The reaction mixture was neutralized with aqueous sodiumhydrogencarbonate and extracted twice with chloroform. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled away under reduced pressure. The residue was purified bysilica gel column chromatography. The solvent was distilled away and thecrystals obtained were recrystallized from diisopropyl ether to give 1.0g of6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinehaving a melting point of 175°-176° C.

Preparation of Starting Material-3

In the same manner as in Preparation of StartingMaterial-2,6-amino-4-(2-chlorophenyl)-2-ethyl-9-phenyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinewas obtained from4-(2-chlorophenyl)-2-ethyl-9-phenyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine.

Preparation of Starting Material-4

In the same manner as in Preparation of StartingMaterial-2,6-amino-4-(2-chlorophenyl)-9-cyclopentyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinewas obtained from4-(2-chlorophenyl)-9-cyclopentyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.

Preparation of Starting Material-5

In the same manner as in Preparation of StartingMaterial-2,6-amino-4-(2-chlorophenyl)-9-cyclopropyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinewas obtained from4-(2-chlorophenyl)-9-cyclopropyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.

Preparation of Starting Material-6

4-(2-Chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(3.4 g) and sodium hydride (0.56 g) were added to diethyl carbonate (50ml) and the mixture was heated. After refluxing for 1 hour, the reactionmixture was cooled to room temperature and3-bromo-N-phthaloylpropylamine (2.3 g) was added thereto. The mixturewas refluxed for 1 hour and the reaction mixture was poured into icewater. The diethyl carbonate layer was separated, washed twice withwater, and dried over anhydrous magnesium sulfate. Diethyl carbonate wasdistilled away under reduced pressure and the residue was purified bysilica gel column chromatography to give 2.4 g ofethyl(4-(2-chlorophenyl)-2-ethyl-9-cyclohexyl-6-(N-phthalylpropylamino)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylate.Ethyl(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6-(N-phthalylpropylamino)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylate(2.4 g) was dissolved in a mixture of ethanol (60 ml) and water (20 ml)and barium hydroxide 8 hydrate (1.14 g) was added thereto. The mixturewas stirred at room temperature for 24 hours. The solvent was distilledaway under reduced pressure and water (50 ml) was added thereto. Themixture was adjusted to pH 2 with 1N hydrochloric acid. After stirringfor 1 hour, the mixture was neutralized with aqueous sodiumhydrogencarbonate and extracted twice with chloroform. The organic layerwas dried over anhydrous magnesium sulfate and the solvent was distilledaway under reduced pressure. The residue was dissolved in ethanol (50ml), and hydrazine hydrate (1.25 g) was added thereto. The mixture wasrefluxed for 3 hours. After the reaction, ethanol was distilled awayunder reduced pressure and chloroform and water were added to theresidue to allow precipitation of crystals. The crystals were filteredoff and the chloroform layer was washed with a saturated aqueoussolution of sodium bicarbonate. The chloroform layer separated was driedover anhydrous magnesium sulfate. The solvent was distilled away underreduced pressure and the residue was purified by silica gel columnchromatography to give 1.2 g of6-(3-aminopropyl)-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.

EXAMPLE 4

6-Amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(0.6 g) was dissolved in chloroform (15 ml) and 4-methoxyphenylisocyanate (0.2 ml) was added thereto. The mixture was stirred for 30minutes. The reaction mixture was purified by silica gel columnchromatography and crystals obtained were recrystallized from methanolto give 0.49 g ofN-(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(4-methoxyphenyl)ureahaving a melting point of 268°-269° C.

EXAMPLE 5

In the same manner as in Example 4,N-(2-chlorophenyl)-N'-(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ureahaving a melting point of 260° C. was obtained from6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineand (2-chlorophenyl)-isocyanate.

EXAMPLE 6

In the same manner as in Example 4,N-(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)ureahaving a melting point of 259°-260° C. was obtained from6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineand (3-chlorophenyl)isocyanate.

Reference Example 1

In a nitrogen atmosphere,4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(1 g) was dissolved in diethyl carbonate (35 ml) and 60% sodium hydridewas added thereto at room temperature with stirring. After refluxingunder heating for 2 hours, the reaction mixture was cooled to roomtemperature and ethyl bromoacetate (0.32 ml) was added thereto. Afterstirring at room temperature for 3 hours, the reaction mixture waspoured into cold water and extraceted with ethyl acetate. The extractwas washed with water, dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography and the objective fraction wasconcentrated under reduced pressure. The residue concentrated wassuspended in a mixture of ethanol (90 ml) and water (30 ml). To thesuspension was added barium hydroxide 8 hydrate (0.65 g) at roomtemperature with stirring and the mixture was stirred at roomtemperature for 10 hours. The reaction mixture was concentrated underreduced pressure and water was added to the residue. The mixture waswashed with ethyl acetate. The aqueous layer was adjusted to pH 2 with6N hydrochloric acid and allowed to stand at room temperature overnight.The reaction mixture was neutralized with sodium hydrogencarbonate andextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure and isopropyl ether was added for crystallization. As aresult, 0.15 g of(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (0.15 g) was obtained as pale brown crystals, melting point198°-202° C.

Reference Example 2

5-(2-Chlorophenyl)-7-ethyl-1-methyl-2-oxo-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-3-yl)aceticacid having a melting point of 228°-231° C. was obtained from5-(2-chlorophenyl)-7-ethyl-1-methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-oneby the same reaction and treatment as in Reference Example 1.

EXAMPLE 7

(4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (2 g) obtained in Reference Example 1 was dissolved indimethylformamide (50 ml), and aniline (0.59 ml), triethylamine (1.4 ml)and 1-hydroxybenzotriazole (0.75 g) were added thereto at roomtemperature with stirring. The mixture was cooled to 0° C. or below withstirring and N-ethyl-N'-(3-dimethylaminomethyl)carbodiimidehydrochloride (1.05 g) was added thereto. The mixture was heated to roomtemperature and allowed to stand overnight. The reaction mixture waspoured into water and extrated with ethyl acetate. The organic layer waswashed with 1N acetic acid, 1N sodium hydroxide and water, and driedover an hydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure, and crystals obtained wererecrystallized from ethanol to give 1.4 g ofN-phenyl-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidehaving a melting point of 238°-239° C.

The following compounds were obtained in the same manner as above.

EXAMPLE 8

N-(3-Methylphenyl)-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-acetamide,melting point 247°-248° C.

EXAMPLE 9

N-(3-Chlorophenyl)-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide, melting point 217°-218° C.

EXAMPLE 10

N-(2-Methoxyphenyl)-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide,melting point 198°-200° C.

EXAMPLE 11

N-(3-Methoxyphenyl)-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide,melting point 244° C.

EXAMPLE 12

6-Amino-4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(1.6 g) was dissolved in chloroform (8 ml) and triethylamine (0.69 ml)was added thereto with stirring. p-Toluenesulfonyl chloride (0.94 g) wasadded thereto with stirring at room temperature and the mixture wasrefluxed under heating with stirring for 2 hours in an oil bath. Aftercooling, the reaction mixture was concentrated under reduced pressureand the residue was purified by silica gel column chromatography. Theobjective fraction was concentrated under reduced pressure and isopropylether was added to the residue for crystallization. As a result, 1.25 gof crystals ofN-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-p-toluenesulfonamidehaving a melting point of 239°-242° C. was obtained.

The following compound was obtained in the same manner as above.

EXAMPLE 13

N-(4-(2-Chlorophenyl)-2-(4-isobutylphenyl)ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-p-toluenesulfonamide,melting point 158°-162° C.

EXAMPLE 14

5-(2-Chlorophenyl)-7-ethyl-1-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one(3 g) was dissolved in chloroform (60 ml) and m-chloroperbenzoic acid(4.3 g) was added thereto with stirring at room temperature. The mixturewas further stirred for 8 hours. The reaction mixture was washed with0.5N sodium hydroxide and water and dried over magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure and theresidue obtained was dissolved in acetic anhydride (30 ml). The mixturewas stirred while heating at 70° C. After cooling, the reaction mixturewas poured into water and neutralized with sodium hydrogen-carbonate.After the mixture was extracted with ethyl acetate, the organic layerwas washed with an aqueous solution of sodium hydrogencarbonate andwater, and dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the residue wasdissolved in methanol (40 ml). A solution of sodium hydroxide (0.6 g) inwater (10 ml) was added thereto at room temperature with stirring andthe mixture was stirred at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure and water (50 ml) wasadded thereto. After the mixture was extracted with ethyl acetate, theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography to give 1.3 g of crude5-(2-chlorophenyl)-7-ethyl-3-hydroxy-1-methyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one.This compound (0.7 g) was dissolved in toluene (20 ml) and3-methylphenylisocyanate (0.31 g) was added thereto. The mixture wasstirred for 2 days while heating at 90° C. After cooling, the reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography to give 0.25 g of(5-(2-chlorophenyl)-7-ethyl-1-methyl-oxo-1,3-dihydro-2H-thieno[2,3-e][1,4]-diazepin-3-yl)-N-(3-methylphenyl)carbamatehaving a melting point of 181°-182.5° C.

The following compound was obtained in the same manner as above.

EXAMPLE 15

(4-(4-Methoxyphenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-methylphenyl)carbamate,melting point 190°-192° C.

Reference Example 3

4-Methoxycyanoacetophenone (89 g) and sulfur (16 g) were suspended indimethylformamide (200 ml) and butyraldehyde (36.1 g) was added theretounder ice-cooling. Then, triethylamine (50.6 g) was added thereto andthe mixture was allowed to react at 50°-55° C. for 1.5 hours withstirring. The reaction mixture was poured into ice water and extractedwith ethyl acetate (1500 ml). The extract was washed with water anddried over anhydrous magnesium sulfate. After filtration, the filtratewas concentrated under reduced pressure and crystallized fromhexane-isopropyl ether (4:1) to give 110 g of2-amino-5-ethyl-3-(4-methoxybenzoyl)-thiophene as dark brown crystals.

The compound (110 g) obtained as above was dissolved in chloroform (400ml) and chloroacetyl chloride (50.1 g) was added thereto with stirring.The mixture was refluxed for 1 hour under heating with stirring. Aftercooling, the reaction mixture was washed with 5% aqueous sodiumhydrogencarbonate and water, and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureand crystallized from isopropyl ether to give 125 g of2-chloroacetylamino-5-ethyl-3-(4-methoxybenzoyl)thiophene as browncrystals.

Said chloroacetyl compound (125 g) and sodium iodide (62 g) weresuspended in tetrahydrofuran (500 ml) and the suspension was refluxedfor 2 hours under heating with stirring. The reaction mixture was cooledto -50° C. and liquid ammonia (ca. 100 ml) was added thereto at oncewith stirring. The temperature of the reaction mixture was raised toroom temperature over 2 hours. After removing ammonia with an aspirator,the reaction mixture was concentrated under reduced pressure and theresidue was dissolved in isopropyl alcohol (500 ml). Thereto was addedacetic acid (26.7 g) and the mixture was refluxed for 14 hours underheating with stirring. After concentration under reduced pressure, theresidue was dissolved in chloroform (500 ml), and washed with 5% aqueoussodium hydrogencarbonate and saline, and dried over anhydrous magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and the residue was crystallized from isopropyl ether-ethylacetate (5:1) to give 52 g of7-ethyl1,3-dihydro-5-(4-methoxyphenyl)thieno[2,3-e][1,4]diazepin-2-oneas yellow crystals.

The diazepine compound (52 g) obtained as above was dissolved indichloromethane (500 ml), and phosphorus pentasulfide (46 g) was addedthereto. The mixture was refluxed for 3 hours under heating withstirring. After cooling, the reaction mixture was washed with 5% aqueoussodium hydrogencarbonate and water, and dried over anhydrous magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure to give7-ethyl-5-(4-methoxyphenyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepine-2-thioneas an oily substance.

The thione compound obtained as above was suspended in methanol (600 ml)and 100% hydrazine hydrate (25.1 ml) was added thereto under ice-coolingwith stirring. The mixture was stirred at room temperature for 1 hourand concentrated under reduced pressure. The residue was crystallizedfrom isopropyl ether to give 39 g of7-ethyl-2-hydrazino-5-(4-methoxyphenyl)-3H-thieno[2,3-e][1,4]diazepineas reddish brown crystals.

Reference Example 4

4-Methylcyanoacetophenone (120 g) and sulfur (24.2 g) were suspended indimethylformamide (300 ml) and butyraldehyde (54.4 g) was added thereto.Then, triethylamine (76.3 g) was added thereto and the mixture wasreacted at 70° C. for 1.5 hours with stirring. The reaction mixture waspoured into ice water, extracted with ethyl acetate, washed with waterand dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give 244 g of2-amino-5-ethyl-3-(4-methylbenzoyl)thiophene as dark brown crystals.

Said compound (244 g) was dissolved in chloroform (1200 ml) andchloroacetyl chloride (112 g) was added thereto with stirring. Themixture was stirred at room temperature for 1 hour. The reaction mixturewas washed with 5% aqueous sodium hydrogencarbonate and water, and driedover anhydrous magnesium sulfate.

After filtration, the residue obtained by concentration under reducedpressure was suspended in tetrahydrofuran (1000 ml) and sodium iodide(149 g) was added thereto. The mixture was refluxed under heating withstirring for 2 hours. The reaction mixture was cooled to -50° C. andliquid ammonia (ca. 120 ml) was added at once with stirring. Thetemperature of the reaction mixture was raised to room temperature over2 hours. After removing ammonia with an aspirator, the reaction mixturewas concentrated under reduced pressure and the residue was dissolved inisopropyl alcohol (1200 ml). Thereto was added acetic acid (72 g) andthe mixture was allowed to react at 70° C. for 14 hours with stirring.After concentration under reduced pressure, the residue was dissolved inchloroform (1000 ml), washed with 5% aqueous sodium hydrogencarbonateand saline and dried over anhydrous magnesium sulfate. After filtration,the filtrate was concentrated under reduced pressure and the residue waspurified by silica gel chromatography to give 25 g of7-ethyl-1,3-dihydro-5-(4-methylphenyl)-thieno[2,3-e][1,4]diazepin-2-one.

The aforementioned diazepine compound (25 g) was dissolved in chloroform(300 ml) and phosphorus pentasulfide (7.5 g) was added thereto, followedby reflux under heating with stirring for 3 hours. After cooling, themixture was washed with 5% aqueous sodium hydrogencarbonate and waterand dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give 20 g of7-ethyl-5-(4-methylphenyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepine-2-thioneas orange crystals.

The thione compound (20 g) as mentioned above was suspended in methanol(100 ml) and 100% hydrazine hydrate (13.2 g) was added thereto. Themixture was stirred at room temperature for 0.5 hour. Concentrationunder reduced pressure gave 18.3 g of7-ethyl-2-hydrazino-5-(4-methylphenyl)-3H-thieno[2,3-e][1,4]diazepine asred brown crystals.

Reference Example 5

2-Aminobenzophenone (25 g) was dissolved in chloroform (250 ml) andchloroacetyl chloride (17.2 g) was added thereto with stirring. Themixture was refluxed under heating for 1 hour. The reaction mixture waswashed with water and dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure and theresidue was suspended in tetrahydrofuran (250 ml). Thereto was addedsodium iodide (28.6 g) and the mixture was refluxed under heating withstirring for 2 hours.

The reaction mixture was cooled to -50° C. and liquid ammonia (ca. 50ml) was added at once with stirring. The temperature of the reactionmixture was raised to room temperature over 2 hours. After removingammonia with an aspirator, the reaction mixture was distilled underreduced pressure and ethyl acetate (250 ml) was added thereto. Afterwashing with water, the mixture was dried over magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was dissolved in isopropyl alcohol (300 ml). Thereto was addedacetic acid (9.1 g) and the mixture was refluxed under heating withstirring for 14 hours. After concentration under reduced pressure, theresidue was dissolved in chloroform (300 ml), washed with 5% aqueoussodium hydrogencarbonate and saline, and dried over anhydrous magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and ethyl acetate (100 ml) was added to the residue to allowcrystallization to give 21 g of1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one as crystals.

The aforementioned diazepine compound (18 g) was dissolved in dioxane(150 ml) and phosphorus pentasulfide (6.8 g) was added thereto, followedby reflux under heating with stirring for 2 hours. After cooling, themixture was washed with 5% aqueous sodium hydrogencarbonate and salineand dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give 10.6 g of1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione.

The thione compound (5.5 g) mentioned above was suspended in methanol(50 ml) and 100% hydrazine hydrate (2.1 ml) was added thereto withstirring under ice-cooling. The mixture was stirred at room temperaturefor 3 hours. Concentration under reduced pressure gave 5.0 g of ahydrazono compound as an oily substance.

EXAMPLE 16

The hydrazono compound (5 g) obtained in Reference Example 3 wassuspended in chloroform (100 ml) and n-dodecanoyl chloride (4.2 g) wasadded thereto. The mixture was stirred at room temperature for 1 hour.After washing with 5% aqueous sodium hydrogencarbonate and water, themixture was dried over anhydrous magnesium sulfate. After filtration,the filtrate was concentrated under reduced pressure and the residue wasdissolved in toluene (100 ml). Thereto was added acetic acid (1.1 ml)with stirring and the mixture was refluxed under heating with stirringfor 1 hour. After cooling, the reaction mixture was washed with 5%aqueous sodium hydrogencarbonate and water, and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The residue obtained was crystallized from isopropylether to give 7.8 g of2-ethyl-4-(4-methoxylphenyl)-9-undecyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineas white crystals.

EXAMPLE 17

Anhydrous aluminum chloride (78.1 g) was suspended in dichloromethane(700 ml) and thereto was dropwise added n-butylmercaptan (106 ml) withstirring under ice-cooling. Thereto was added2-ethyl-4-(4-methoxylphenyl)-9-undecyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(40 g) obtained in Example 1 under ice-cooling. After stirring at roomtemperature for 20 hours, the reaction mixture was washed with 5%aqueous sodium hydrogencarbonate and water and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure and purified by silica gel column chromatography togive 20 g of2-ethyl-4-(4-hydroxyphenyl)-9-undecyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineas crystals, melting point 164.5°-166.5° C.

EXAMPLE 18

The hydrazono compound (6 g) obtained in Reference Example 4 wassuspended in chloroform (50 ml) and thereto was added stearyl chloride(6.7 g). The mixture was stirred at room temperature for 1 hour. Afterwashing with 5% aqueous sodium hydrogencarbonate and water, the mixturewas dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure and the residue wasdissolved in toluene (100 ml). Thereto was added acetic acid (1.25 ml)with stirring and the mixture was refluxed under heating with stirringfor 1 hour. After cooling, the mixture was washed with 5% aqueous sodiumhydrogencarbonate and water and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureand the residue was purified by silica gel column chromatography. Theobtained oily substance was crystallized from ethyl acetate-hexane togive2-ethyl-9-heptadecyl-4-(4-methylphenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepineas white crystals, melting point 78°-80° C.

EXAMPLE 19

The hydrazono compound (5.0 g) obtained in Reference Example 5 wassuspended in chloroform (50 ml) and thereto was added n-dodecanoylchloride (5.8 g). The mixture was stirred at room temperature for 1hour. After washing with 5% aqueous sodium hydrogencarbonate and water,the reaction mixture was dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure and theresidue was dissolved in toluene (50 ml). Thereto was added acetic acid(1.5 ml) with stirring and the mixture was refluxed under heating withstirring for 1 hour. After cooling, the mixture was washed with 5%aqueous sodium hydrogencarbonate and water and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography. The oily substance obtained was crystallized from hexaneto give 3.4 g of6-phenyl-1-undecyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine as whitecrystals, melting point 76°-77° C.

EXAMPLE 20

2-Ethyl-4-(4-methoxylphenyl)-9-undecyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(8.0 g) obtained in Example 16 was suspended in water (200 ml). Theretowas added sulfuric acid (7.6 ml) and the mixture was stirred at 80° C.for 2 hours. Thereto was gradually added dropwise a solution of sodiumnitrite (7.6 g) in water (25 ml) and the mixture was stirred at 80° C.for 3 hours. After cooling, potassium carbonate was added thereto tomake the reaction mixture alkaline. The mixture was extracted with ethylacetate, washed with water and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureand the residue was purified by silica gel column chromatography to give4.4 g of5-ethyl-3-(4-methoxybenzoyl)-2-(3-hydroxymethyl-5-undecyl1,2,4-triazol-4-yl)thiopheneas an oily substance.

EXAMPLE 21

2-Ethyl-4-(4-hydroxyphenyl)-9-undecyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(20 g) obtained in Example 17 was dissolved in dioxane (300 ml). Theretowere added water (300 ml) and sulfuric acid (12 ml) and the mixture wasstirred at 80° C. for 2 hours. Thereto was gradually added dropwise asolution of sodium nitrite (30 g) in water (100 ml) and the mixture wasstirred at 80° C. for 3 hours. After cooling, potassium carbonate wasadded thereto to make the reaction mixture alkaline. The mixture wasextracted with ethyl acetate, washed with water and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure and purified by silica gel column chromatography togive 11 g of5-ethyl-3-(4-hydroxybenzoyl)-2-(3-hydroxymethyl-5-undecyl1,2,4-triazol-4-yl)thiopheneas an oily substance.

EXAMPLE 22

2-Ethyl-9-heptadecyl-4-(4-methylphenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(6 g) obtained in Example 18 was dissolved in dioxane (60 ml). Theretowere added water (60 ml) and sulfuric acid (2.9 ml) and the mixture wasstirred at 80° C. for 2 hours. A solution of sodium nitrite (7.6 g) inwater (25 ml) was gradually added dropwise and the mixture was stirredat 80° C. for 3 hours. After cooling, potassium carbonate was addedthereto to make the reaction mixture alkaline. The mixture was extractedwith ethyl acetate, washed with water and dried over anhydrous magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography. The oily substance obtained was crystallized from hexaneto give 0.6 g of5-ethyl-3-(4-methylbenzoyl)-2-(5-heptadecyl-3-hydroxymethyl-1,2,4-triazol-4-yl)thiopheneas white crystals, melting point 68°-69° C.

EXAMPLE 23

6-phenyl-1-undecyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (3.2 g)obtained in Example 19 was dissolved in dioxane (30 ml). Thereto wereadded water (30 ml) and sulfuric acid (2.1 ml) and the mixture wasstirred at 60° C. for 1 hour. Thereto was gradually added dropwise asolution of sodium nitrite (5.5 g) in water (20 ml) and the mixture wasstirred at 70° C. for 2 hours. After cooling, potassium carbonate wasadded thereto to make the reaction mixture alkaline. The mixture wasextracted with ethyl acetate, washed with water and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography to give 0.4 g of2-(3-hydroxymethyl-5-undecyl1,2,4-triazol-4-yl)benzophenone as an oilysubstance, melting point 111°-112° C.

EXAMPLE 24

5-Ethyl-3-(4-methoxybenzoyl)-2-(3-hydroxymethyl-5-undecyl-1,2,4-triazol-4-yl)thiophene(4.4 g) obtained in Example 20 was dissolved in ethanol (100 ml).Thereto was added sodium borohydride (0.16 g) with stirring and themixture was stirred at room temperature for 1 hour. After the ethanolwas distilled away, 5% aqueous sodium hydrogencarbonate was addedthereto and the liberated oily substance was extracted with ethylacetate. The extract was washed with water and dried over anhydrousmagnesium sulfate. After filtration, the filtrate was concentrated underreduced pressure and toluene (100 ml) was added to the residue. Themixture was refluxed under heating with stirring and sulfuric acid wasgradually added dropwise until the reaction ended. After cooling, 5%aqueous sodium hydrogencarbonate was added thereto and the mixture wasextracted with ethyl acetate. The extract was washed with water anddried over anhydrous magnesium sulfate. After filtration, the residuewas concentrated under reduced pressure and the residue was purified bysilica gel column chromatography. The oily substance obtained wascrystallized from hexane to give 1.64 g of2-ethyl-4-(4-methoxyphenyl)-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepineas white crystals, melting point 91°-93° C.

EXAMPLE 25

5-Ethyl-3-(4-hydroxybenzoyl)-2-(3-hydroxymethyl-5-undecyl-1,2,4-triazol-4-yl)thiophene(11 g) obtained in Example 21 was dissolved in ethanol (60 ml). Theretowas added sodium borohydride (431 mg) with stirring and the mixture wasstirred at room temperature for 1 hour. After the ethanol was distilledaway, 5% aqueous sodium hydrogencarbonate was added to the residue andthe liberated oily substance was extracted with ethyl acetate. Theextract was washed with water and dried over anhydrous magnesiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and toluene (150 ml) was added to the residue. The mixture wasrefluxed under heating with stirring and sulfuric acid was graduallyadded dropwise until the reaction ended. After cooling, 5% aqueoussodium hydrogencarbonate was added thereto and the mixture was extractedwith ethyl acetate. The extract was washed with water and dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the oily substance obtained wascrystallized from isopropyl etherethyl acetate (4:1) to give 6.5 g of2-ethyl-4-(4-hydroxyphenyl)-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepineas white brown crystals, melting point 96°-98° C.

EXAMPLE 26

5-Ethyl-3-(4-methylbenzoyl)-2-(5-heptadecyl-3-hydroxymethyl-1,2,4-triazol-4-yl)thiophene(3 g) obtained in Example 22 was dissolved in ethanol (30 ml). Theretowas added sodium borohydride (0.1 g) with stirring and the mixture wasstirred at room temperature for 1 hour. After the ethanol was distilledaway, 5% aqueous sodium hydrogencarbonate was added thereto and theliberated oily substance was extracted with ethyl acetate. The extractwas washed with water and dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure andtoluene (120 ml) was added to the residue. The mixture was refluxedunder heating with stirring and sulfuric acid was gradually addeddropwise until the reaction ended. After cooling, 5% aqueous sodiumhydrogencarbonate was added thereto and the mixture was extracted withethyl acetate. The extract was washed with water and dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel chromotography. The oily substance obtained was crystallizedfrom hexane to give 0.9 g of2-ethyl-9-heptadecyl-4-(4-methylphenyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepineas white crystals, melting point 83°-84° C.

EXAMPLE 27

2-(3-Hydroxymethyl-5-undecyl1,2,4-triazol-4-yl)benzophenone (2.7 g)obtained in Example 23 was dissolved in ethanol (30 ml). Thereto wasadded sodium borohydride (240 mg) with stirring and the mixture wasstirred at room temperature for 2 hours. After the ethanol was distilledaway, 5% aqueous sodium hydrogencarbonate was added thereto and theliberated oily substance was extracted with ethyl acetate. The extractwas washed with water and dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure andtoluene (150 ml) was added to the residue. The mixture was refluxedunder heating with stirring and sulfuric acid was gradually addeddropwise until the reaction ended. After cooling, 5% aqueous sodiumhydrogencarbonate was added thereto and the mixture was extracted withethyl acetate. The extract was washed with water and dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel chromotography. The oily substance obtained was crystallizedfrom hexane to give 1 g of6-phenyl-1-undecyl-4H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazepine,melting point 83°-84° C.

Reference EXAMPLE 6

phosphonium salt (141 g) obtained from n-nonyl bromide (115 ml) andtriphenylphosphine (78.5 g) was dissolved in dry tetrahydrofuran (500ml) and thereto was dropwise added n-butyl lithium (372 ml, 1.6M hexanesolution) over not less than 1 hour at 0° C. After the dropwiseaddition, the reaction mixture was stirred at said temperature for 30minutes and at room temperature for 1 hour. A solution of4-nitrobenzaldehyde (45.3 g) in tetrahydrofuran (150 ml) was dropwiseadded thereto at 0° C. over 1 hour. The reaction mixture was stirred atroom temperature for 10 hours and filtered. The residue was washed withether. The filtrate was concentrated under reduced pressure and purifiedby silica gel column chromatography (hexane/ethyl acetate=100:1) to give70.9 g of 4-(1-decenyl)nitrobenzene (cis/trans=7:3).

A mixture of 4-(1-decenyl)nitrobenzene (12.2 g), acetic acid (120 ml)and palladium black (0.84 g) was hydrogenated at room temperature and at3-4 atm for 12 hours. The catalyst was changed and the reaction wascontinued under the same conditions for 12 hours. The catalyst wasfiltered off and the filtrate was concentrated under reduced pressure togive 10.9 g of 4-decylaniline.

A solution of 4-decylaniline (4.50 g) in dry benzene (20 ml) wasdropwise added to a solution of boron trichloride (21.2 ml, 1M methylenechloride solution) in dry benzene (10 ml) under ice-cooling. After thedropwise addition, benzonitrile (2.96 ml) and aluminum chloride (2.83 g)were added in order and the mixture was stirred at room temperature for20 minutes, followed by reflux under heating overnight. After cooling,2N hydrochloric acid was added thereto and the mixture was stirred at80° C. for 30 minutes. The residue was filtered off and the filtrate wasextracted with ether and dried over anhydrous magnesium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure and theresidue was purified by silica gel chromotography (hexane/ethylacetate=:10:1) to give 2.89 g of 2-amino-5-decylbenzophenone.

Reference Example 7

phosphonium salt (141 g) obtained from n-nonyl bromide (115 ml) andtriphenylphosphine (78.5 g) was dissolved in dry tetrahydrofuran (500ml) and thereto was dropwise added n-butyl lithium (372 ml, 1.6M hexanesolution) over not less than 1 hour at 0° C. After the dropwiseaddition, the reaction mixture was stirred at said temperature for 30minutes and at room temperature for 1 hour, and a solution of3-nitrobenzaldehyde (45.3 g) in tetrahydrofuran (150 ml) was dropwiseadded thereto at 0° C. over 1 hour. The reaction mixture was stirred atroom temperature for 10 hours and filtered. The residue was washed withether. The filtrate was concentrated under reduced pressure and purifiedby silica gel column chromatography (hexane/ethyl acetate=100:1) to give57.3 g of 3-(1-decenyl)nitrobenzene (cis/trans=7:3).

A mixture of 3-(1-decenyl)nitrobenzene (43.9 g), acetic acid (200 ml)and palladium black (2.0 g) was hydrogenated at room temperature and atatmospheric pressure for 12 hours. The catalyst was changed and thereaction was continued for 12 hours under the same conditions. Thecatalyst was filtered off and the residue was concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (hexane/chloroform=10:1→1:2) to give 7.36 g of3-decylaniline.

A solution of 3-decylaniline (3.82 g) in dry benzene (10 ml) wasdropwise added to a solution of boron trichloride (36 ml, 1M methylenechloride solution) in dry benzene (10 ml) under ice-cooling. After thedropwise addition, benzonitrile (2.51 ml) and aluminum chloride (4.80 g)were added in order and the mixture was stirred at room temperature for2 hours, followed by reflux under heating overnight. Thereto were addedboron trichloride (18 ml, 1M methylene chloride solution), benzonitrile(2.5 ml) and aluminum chloride (2.4 g) and the mixture was refluxedunder heating for 16 hours. After cooling, 2N hydrochloric acid (42 ml)was added thereto and the mixture was stirred at 80° C. for 45 minutes.The residue was filtered off and the filtrate was extracted with etherand dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure and the residue waspurified by silica gel chromotography (hexane/ethyl acetate=10:1) togive 4.16 g of 2-amino-4-decylbenzophenone.

EXAMPLE 28

(±)-4-Amino-6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(300 mg) and activated charcoal (30 mg) were suspended in anhydrousmethylene chloride (2 ml). Thereto was added trichloromethylchloroformate (0.09 ml) and the mixture was allowed to react withphosgene evolved in the reaction system, at room temperature for 1.5hours. After the termination of the reaction, the reaction mixture wasfiltered through celite and 2-aminopyridine (130 mg) was added to thefiltrate. The mixture was reacted at room temperature for 1 hour andconcentrated under reduced pressure. The crystals obtained wererecrystallized from N,N-dimethylformamide/water to give 84 mg of(±)-N-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N'-(2-pyridyl)ureaas colorless crystals, mp. 274°-278° C.

EXAMPLE 29

A solution of aniline (0.22 ml) in methylene chloride (3 ml) wasdropwise added to a solution of oxalyl chloride (0.42 ml) in methylenechloride (8 ml) under ice-cooling over 5 minutes. The mixture wasstirred at said temperature for 10 minutes, added with triethylamine(0.33 ml) and stirred for 1 hour. The reaction mixture was concentratedto dryness under reduced pressure. Methylene chloride (8 ml) was addedto the residue and the mixture was ice-cooled. Thereto was dropwiseadded a solution of4-amino-6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(208 mg) in methylene chloride (2 ml) over 5 minutes. The reactionmixture was stirred at room temperature for 2 hours. Thereto was addedchloroform (5 ml) and the reaction mixture was washed with water,aqueous sodium hydrogencarbonate and water in order. The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated to dryness and the residue was purified by silica gelchromotography (developing solvent; chroloform/methanol=50:1) and theobtained pure fraction was concentrated to dryness. The concentrate wasthen crystallized from a mixed solvent of ethyl acetate-ether to give99.0 mg of(±)-N-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N'-phenyloxalyldiamideas colorless needle crystals, mp. 247°-248° C.

EXAMPLE 30

Phenyl hydrazine (0.5 ml) was added to a solution of(±)-6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(190 mg) in dimethyl sulfoxide (5 ml), and the mixture was stirred at90° C. for 2 days. Thereto was added chloroform (50 ml) and the reactionmixture was washed with water, 0.3N hydrochloric acid and water inorder. The chloroform layer was dried and concentrated to dryness. Theresidue was purified by silica gel chromotography(chroloform/methanol=30:1) and the obtained pure fraction wasconcentrated. Thereto was added ethyl acetate to give the objectivecrystals. The crystals were recrystallized from a mixed solvent ofchloroform-ethyl acetate to give 134.3 mg of pure(±)-N'-phenyl-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]carbohydrazideas colorless needle crystals, mp. 175°-177° C.

In the same manner, hydrazine (H₂ NNH₂) was added to a solution of(±)-6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(660 mg) in dimethylformamide (7 ml) and the mixture was reacted at roomtemperature for 1 hour. The mixture was extracted in the same manner asabove and the residue was crystallized from chloroform-ether to give 415mg of(±)-6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl)carbohydrazideas colorless needle crystals, mp. 175°-178° C.

EXAMPLE 31

Benzoyl chloride (64 ml) was added to a solution of(±)-N-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]carbohydrazide(183 mg) in pyridine (4 ml) under ice-cooling. After stirring themixture at said temperature for 30 minutes, water (0.1 ml) was addedthereto and the mixture was stirred for 10 minutes. Pyridine wasdistilled away under reduced pressure and the residue was dissolved inchloroform and washed with water. The organic layer was dried,concentrated and added with ethyl acetate to give 195 mg of crystals.The crystals were recrystallized from a mixed solvent of chlorofom-ethylacetate to give 164.4 mg of pure(±)-N'-benzoyl-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]carbohydrazideas colorless needle crystals, mp. 243°-245° C.

EXAMPLE 32

A solution of(±)-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]carbohydrazide(109.7 mg) in dimethylformamide (1 ml) was cooled to -40° C. and 4Ndioxane hydrochloride (0.23 ml) was added thereto. The temperature ofthe mixture was raised to 0° C. The reaction mixture was cooled again to-40° C. and isopentyl nitrite (40 μl) was added thereto. The mixture wasstirred at -30° C. for 1 hour. The temperature of the mixture was againcooled to -70° C. Triethylamine (0.125 ml) was added to the mixture and10 minutes later, benzyl amine (77 μl) was added thereto. Then, thetemperature of the mixture was raised to 0° C. and the mixture wasstirred for 3 hours. The mixture was stirred at room temperature for 10hours. Dimethylformamide was distilled away under reduced pressure andthe residue obtained was dissolved in chloroform and washed with 0.3Nhydrochloric acid, an aqueous solution of sodium bicarbonate and waterin order and dried over anhydrous sodium sulfate. Chloroform wasdistilled away under reduced pressure and ethyl acetate was added to theresidue to give 95.1 mg of(±)-N-benzyl-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepin-4-yl]carboxamide as colorless needle crystals, mp.265°-267° C.

In the same manner,(±)-O-benzyl-N-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]carbohydroxamatewas synthesized, mp. 138°-139° C.

EXAMPLE 33

In a nitrogen atmosphere,4-amino-6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine(373 mg) was dissolved in dry tetrahydrofuran (4 ml) and thereto wasadded 3-methylphenyl isocyanate (139 μl), followed by reaction at roomtemperature for 3.5 hours. After the completion of the reaction, waterwas added to the reaction mixture and the mixture was extracted withethyl acetate. The organic layer was washed with a 5% aqueous solutionof citric acid, water and saturated brine, and dried over anhydrousmagnesium sulfate. The residue was concentrated under reduced pressure.The concentrate was purified by silica gel column chromatography(chroloform:methanol=45:1) and crystallized to give 219 mg ofN-[6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N'-(3-methylphenyl)ureaas pale yellow needle crystals, mp. 168°-172° C.

EXAMPLE 34

In a nitrogen atmosphere,N-[6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepin-4-yl]-N'-(3-methylphenyl)urea dissolved in anhydroustetrahydrofuran (2 ml) was dropwise added to a suspension of 60% sodiumhydride (10 mg) in anhydrous tetrahydrofuran (1 ml) at room temperatureand the mixture was refluxed under heating for 30 minutes. After thereaction mixture was cooled, water was added thereto and the mixture wasextracted with ethyl acetate. The organic layer was washed with a 5%aqueous solution of citric acid, water and saturated brine and driedover anhydrous magnesium sulfate. The residue was concentrated underreduced pressure. The concentrate was recrystallized from ether-ethylacetate to give 37 mg of6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-spiro-5'-[3'-(3-methylphenyl)-2',4'-dioxoimidazolidine]as colorless needle crystals, mp. 269°-271° C.

EXAMPLE 35

6-(4-Chlorophenyl)-1-undecyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(1.23 g) was dissolved in dichloromethane (10 ml) and acetic acid (5 ml)and zinc powder (540 mg) were added thereto with stirring. Afterstirring at room temperature for 6 hours, the mixture was washed with 5%aqueous sodium hydrogencarbonate and water. The reaction mixture wasdried over anhydrous magnesium sulfate. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography and the oily substance obtained wascrystallized from ethyl acetate to give 320 mg of6-(4-chlorophenyl)-1-undecyl-4H,5H,6H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,mp. 94°-95° C.

EXAMPLE 36

2-Amino-4-decylbenzophenone (4.16 g) was dissolved in chloroform (40 ml)and phthaloylalanyl chloride (3.22 g) was added thereto with stirring atroom temperature. The mixture was stirred for 0.5 hour. The reactionmixture was washed with 5% aqueous sodium hydrogencarbonate and waterand dried over anhydrous magnesium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The concentrate waspurified by silica gel column chromatography and the oily substanceobtained was dissolved in a mixed solvent of methanol (20 ml) andtetrahydrofuran (40 ml). Thereto was added hydrazine monohydrate (1.56g) with stirring under ice-cooling and the mixture was stirred for 2hours. Conc. hydrochloric acid (1 ml) was added thereto with stirring atroom temperature and the mixture was stirred at 60° C. for 2 hours.After cooling, the mixture was concentrated under reduced pressure andthe residue was extracted with chloroform and washed with 5% aqueoussodium hydrogencarbonate and water. The residue was dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. Isopropyl alcohol (60 ml) and acetic acid (1 ml) wereadded to the concentrate and the mixture was stirred at 70° C. for 1hour. After cooling, the residue obtained by concentration under reducedpressure was extracted with chloroform and washed with 5% aqueous sodiumhydrogencarbonate and water. The extract was dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and purified by silica gel column chromatography to give 3.2 gof 8-decyl-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ascrystals.

The thione compound (2.8 g) as mentioned above was suspended in methanol(30 ml) and hydrazine monohydrate (400 μl) was added thereto withstirring at room temperature. The mixture was stirred at roomtemperature for 1 hour. After concentration under reduced pressure, theresidue was dissolved in chloroform, washed with water and dried overanhydrous magnesium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and purified by silica gel columnchromatography to give 1.9 g of a hydrazono compound as an oilysubstance.

The hydrazono compound (1.9 g) obtained was suspended in toluene (20 ml)and thereto was added triethyl orthoacetate (1.6 g). The mixture wasrefluxed under heating for 16 hours. After cooling, the mixture wasextracted with ethyl acetate, washed with 5% aqueous sodiumhydrogencarbonate and water and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated under reduced pressureand purified by silica gel column chromatography. The oily substanceobtained was crystallized from isopropyl ether to give 0.3 g of9-decyl-1,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine,mp. 111°-112° C.

The formulation examples of the preparation of the present invention aregiven in the following.

(1) Tablet

The above-mentioned compound (I) (0.5 part), lactose (25 parts),crystalline cellulose (35 parts) and corn starch (3 parts) arethoroughly mixed and kneaded well with a binder prepared from cornstarch (2 parts). The kneaded composition is passed through a 16-meshsieve, dried in an oven at 50° C. and passed through a 24-mesh sieve.The obtained kneaded powder, corn starch (8 parts), crystallinecellulose (11 parts) and talc (9 parts) are thoroughly mixed andcompressed to give tablets containing 0.5 mg of an active ingredient pertablet.

(2) 1% Powder

The above-mentioned compound (I) (1 part) and lactose (90 parts) arethoroughly mixed and kneaded well with a binder prepared from a suitableamount of methylcellulose. The kneaded composition is passed through a16-mesh sieve and dried in an oven at 50° C. The dry granule was presspassed through a 32-mesh sieve and mixed well with a suitable amount ofsilicon dioxide to give a 1% powder.

We claim:
 1. A method for treating osteoporosis comprising administering an azepine compound or a pharmaceutically acceptable salt thereof of the formula ##STR310## wherein Ar is phenyl;X and Y combinedly form ═N--N═C(R⁶)-- or ═N--N(R⁵)--CO-- wherein R⁵ and R⁶ are each hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aryloxyalkyl, --(CH₂)aCOOR⁷ wherein a is an integer of 1 to 6 and R⁷ is hydrogen, alkyl, alkenyl or aralkyl, or --(CH₂)aNHCOR⁴³ wherein a is an integer of 1 to 6 and R⁴³ is alkyl or aralkyl; W is --N(R³⁶)-- wherein R³⁶ is hydrogen or forms a bond with R³⁵ ; R³⁵ is hydrogen or forms a bond with R is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or a group of a formula selected from the group consisting of:

    --(CH.sub.2)bN(R.sup.8)(R.sup.9)                           (1)

    --(CH.sub.2)bOR.sup.10                                     ( 2) ##STR311##

    --(CH.sub.2)bN(R.sup.10)CORa.sup.11                        ( 4)

    --(CH.sub.2)bN(R.sup.10)SO.sub.2 R.sup.44                  ( 5)

    --(CH.sub.2)bN(R.sup.10)COOR.sup.45                        ( 6) ##STR312##

    --(CH.sub.2)bOCOR.sup.46                                   ( 8)

    --(CH.sub.2)bCON(R.sup.47)(R.sup.48)                       (9)

    --(CH.sub.2)bOSO.sub.2 R.sup.44                            ( 10)

    --(CH.sub.2)bCOR.sup.49                                    ( 11)

    --(CH.sub.2)bS(O)nR.sup.11                                 ( 12)

    --CON(R.sup.10)OR.sup.8                                    ( 13) ##STR313##

    --CON(R.sup.10)N(R.sup.10)SO.sub.2 Ra.sup.11               ( 15) ##STR314##

    --CON(R.sup.10)N(R.sup.10)(R.sup.11)                       (18)

    --(CH.sub.2)bN(R.sup.10)COCON(R.sup.11)(R.sup.12)          (19)

and

    --(CH.sub.2)aCOOR.sup.1                                    ( 20)

wherein b is 0 or an integer of 1 to 6, Z is an oxygen atom or sulfur atom, R⁸ and R⁹ are the same or different and each is hydrogen, alkyl, aryl or aralkyl, R¹⁰ is hydrogen, alkyl or aralkyl, R¹¹ and R¹² are the same or different and each is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, Ra¹¹ is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, R⁴⁴ is alkyl, aryl, aralkyl, cycloalkyl or heteroaryl, R⁴⁵ is alkyl, aryl or aralkyl, R⁴⁶ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, R⁴⁷ and R⁴⁸ are the same or different and each is hydrogen, alkyl, acyl, aryl or aralkyl, R⁴⁹ is alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, n is 0, 1 or 2, a is an integer of 1 to 6 and R¹ is hydrogen, alkyl, aryl or aralkyl; R' is hydrogen or --COOR⁸ wherein R⁸ is hydrogen, alkyl, aryl or aralkyl, ring Q is a ring selected from ##STR315## R¹⁷ and R¹⁸ are the same or different and each is hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, nitro, amino, amino substituted by alkyl, cyclic amino selected from the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl in each of which the nitrogen atom may be substituted by alkyl or aralkyl, hydroxy, acyloxy, cyano, carbamoyl, carbamoyl substituted by alkyl, cyclic aminocarbonyl, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, cycloalkyl, alkylcarbonyl, a group of the formula

    R.sup.19 --A--

wherein A is alkylene, alkenylene or alkynylene each of which may be substituted by 1 to 3 hydroxys and R¹⁹ is alkoxy, nitro, amino, hydroxy, acyloxy, cyano, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkyloxy, alkenyl having 2 to 18 carbon atoms which may be substituted by 1 to 3 hydroxys, alkynyl having 2 to 18 carbon atoms which may be substituted by 1 to 3 hydroxys, aralkenyl having an alkenyl moiety having 2 to 18 carbon atoms which may be substituted by 1 to 3 hydroxys and aralkynyl having an alkynyl moiety having 2 to 18 carbon atoms which may be substituted by 1 to 3 hydroxys, a group of the formula

    (R.sup.20)(R.sup.21)NCO-- or (R.sup.20)(R.sup.21)N--SO.sub.2 --

wherein R²⁰ and R²¹ are the same or different and each is hydrogen, aryl, aralkyl or straight- or branched chain alkyl, alkenyl or alkynyl wherein the alkyl, alkenyl and alkynyl may be substituted by halogen, hydroxy, nitro or amino or R²⁰ and R²¹ may, together with the adjacent nitrogen atom, form a 3 to 7-membered ring which may be substituted by straight- or branched chain alkyl and may have, in the ring, nitrogen, oxygen or sulfur atom as a hetero atom (the additional nitrogen atom may be substituted by straight- or branched chain alkyl having to 1 to 4 carbon atoms, aralkyl or diarylalkyl), a group of the formula

    (R.sup.22)(R.sup.23)N--

wherein R²² and R²³ are the same or different and each is hydrogen, straight- or branched chain alkyl, alkenyl or alkynyl wherein the alkyl, alkenyl and alkynyl may be substituted by halogen, hydroxy, amino, alkylamino, dialkylamino, cyclic amino selected from the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl in each of which the nitrogen atom may be substituted by alkyl or aralkyl, or C-bonded heterocyclic group (carbons may be interrupted by nitrogen, oxygen or sulfur atom), straight- or branched chain alkylcarbonyl which may be mono- or di-substituted by hydroxy, halogen, amino, alkylamino, dialkylamino, cyclic amino selected from the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl in each of which the nitrogen atom may be substituted by alkyl or aralkyl, or straight- or branched chain alkyl (this alkyl may be substituted by halogen or hydroxy), arylcarbonyl, arylsulfonyl, alkylsulfonyl, or R²² and R²³ may form, together with the adjacent nitrogen atom, a saturated or unsaturated 3 to 7-membered ring which may be substituted by straight- or branched chain alkyl and may have, in the ring, nitrogen, oxygen or sulfur atom as a hetero atom (each additional nitrogen atom may be substituted by straight- or branched chain alkyl), a group of the formula ##STR316## wherein R²⁴ is aryl, aralkyl, arylcarbonyl, a group of the formula ##STR317## wherein R²⁵ and R²⁶ are the same or different and each is hydrogen, halogen, haloalkyl, amino, nitro, cyano, hydroxy, alkyl or alkoxy and B is hydrogen, hydroxy or esterified hydroxy, or alkyl having hydroxy and/or carbonyl and X¹ is CH or nitrogen atom, or a group of the formula ##STR318## wherein R²⁷ and R²⁸ are the same or different and each is hydrogen, halogen, haloalkyl, amino, nitro, cyano, hydroxy, alkyl or alkoxy, a group of the formula

    R.sup.29 --(CH.sub.2)d--C.tbd.C--

wherein R²⁹ is aryl or optionally hydrogenated heteroaryl and d is 0, 1 or 2, a group of the formula

    R.sup.29 --O--(CH.sub.2)e--C.tbd.C--

wherein R²⁹ is as defined above and e is 1 or 2, or a group of the formula ##STR319## wherein X⁰ is --OCO--, --CO-- or --N(R⁵¹)CO-- where R⁵¹ is hydrogen or alkyl, m is 0 or 1, R⁵⁰ is alkyl, alkynyl, 2-phenylethynyl, 2-thienylsulfonyl, --(CH₂)aCN where a is an integer of 1 to 6, --(CH₂)b--R⁵² where b is 0 or an integer of 1 to 6 and R⁵² is cycloalkyl, morpholino, thienyl, alkoxy, aryl, imidazolyl or tetrahydropyranyl or SO₂ N(R⁵³) (R⁵⁴) where R⁵³ and R⁵⁴ are the same or different and each is hydrogen, alkyl, or R⁵³ and R⁵⁴, with the adjacent nitrogen atom, form a heterocycle, or adjacent R¹⁷ and R¹⁸ may combinedly form a saturated or unsaturated 5, 6 or 7-membered ring which is condensed to a thiophene ring, said ring being optionally substituted by a substituent Ra³⁰ selected from hydrogen, halogen, alkyl, a group of the formula R¹⁹ --A-- wherein each symbol is as defined above and a group of the formula (R²⁰) (R²¹)NCO-- or (R²⁰) (R²¹)N--SO₂ -- wherein each symbol is as defined above, or R¹⁷ and R¹⁸ may combinedly form a 5, 6 or 7-membered hetero ring which may have oxygen, sulfur or --N(Rb³⁰)-- as a hetero atom; Rb³⁰ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxycarbonyl, alkanoyl, aroyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylaminocarbonyl, a group of the formula R¹⁹ --A-- wherein each symbol is as defined above, a group of the formula (R²⁰ )(R²¹)NCO-- wherein each symbol is as defined above, a group of the formula (R²⁰)(R²¹)N--SO₂ -- wherein each symbol is as defined above, a group of the formula Ra³¹ --SO₂ -- wherein Ra³ 1 is alkyl, phenyl, phenyl substituted by halogen, alkyl, alkoxy, carboxy, alkylsulfonyl, alkylthio, haloalkyl or optionally substituted phenoxy, heteroaryl or naphthyl, a group of the formula ##STR320## wherein Y¹ is oxygen atom or sulfur atom and Rb³¹ is alkenyl, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, phenyl substituted by 1 to 3 substituents selected from alkyl, alkoxy, aryloxy, alkylsulfonyl, halogen and haloalkyl, quinolyl or sulfonyl substituted by phenyl, heteroaryl or naphthyl, or a group of the formula ##STR321## wherein Y¹ is oxygen atom or sulfur atom and Rc³¹ is alkyl, phenyl substituted by phenyl, halogen, alkyl, alkoxy, haloalkyl or phenoxy, or heteroaryl; in the above definitions, phenyl, aryl, aryloxy, aryloxyalkyl, arylcarbonyl, arylsulfonyl, aralkyl, aralkyloxy, aralkyloxycarbonyl, aralkenyl, aralkynyl, diarylalkyl, heteroaryl and heteroarylalkyl may have, on the ring, 1 to 3 substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, nitro, amino, cyano and acyloxy; cycloalkyl of cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl and cycloalkylaminocarbonyl may have 1 to 3 substituents selected from halogen, alkyl, alkoxy, haloalkoxy and aryl.
 2. The method for treating osteoporosis according to claim 1, comprising administering a compound of the formula (I) wherein W is --(NR³⁶)-- where R³⁶ forms a bond with R³⁵, or a pharmaceutically acceptable salt thereof.
 3. The method for treating osteoporosis according to claim 1, comprising administering a compound of the formula (I) wherein W is --N(R³⁶)-- where R³⁶ forms a bond with R³⁵ and X and Y combinedly form ═N--N═C(R⁶)-- where R⁶ is as defined in claim 1, or a pharmaceutically acceptable salt thereof.
 4. The method for treating osteoporosis according to claim 1, comprising administering a compound of the formula (I) wherein W is --N(N³⁶)-- where R³⁶ forms a bond with R³⁵ and X and Y combinedly form ═N--N═C(R⁶ ')-- where R⁶ ' is alkyl having 6 to 20 carbon atoms, or a pharmaceutically acceptable salt thereof.
 5. The method for treating osteoporosis according to claim 1, comprising administering a compound of the formula (I) wherein W is --N(R³⁶)-- where R³⁶ forms a bond with R³⁵, R is alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or a group of a formula selected from the group consisting of:

    --(CH.sub.2)bN(R.sup.8)(R.sup.9)                           (1)

    --(CH.sub.2)bOR.sup.10                                     ( 2) ##STR322##

    --(CH.sub.2)bN(R.sup.10)CORa.sup.11                        ( 4)

    --(CH.sub.2)bN(R.sup.10)SO.sub.2 R.sup.44                  ( 5)

    --(CH.sub.2)bN(R.sup.10)COOR.sup.45                        ( 6) ##STR323##

    --(CH.sub.2)bOCOR.sup.46                                   ( 8)

    --(CH.sub.2)bCON(R.sup.47)(R.sup.48)                       (9)

    --(CH.sub.2)bOSO.sub.2 R.sup.44                            ( 10)

    --(CH.sub.2)bOOR.sup.49                                    ( 11)

    --(CH.sub.2)bS(O)nR.sup.11                                 ( 12)

    --CON(R.sup.10)OR.sup.8                                    ( 13) ##STR324##

    --CON(R.sup.10)N(R.sup.10)SO.sub.2 Ra.sup.11               ( 15) ##STR325##

    --CON(R.sup.10)N(R.sup.10)(R.sup.11)                       (18)

    --(CH.sub.2)bN(R.sup.10)COCON(R.sup.11)(R.sup.12)          (19)

and

    --(CH.sub.2)aCOOR.sup.1                                    ( 20)

wherein each symbol is as defined in claim 1 and the ring Q is a group of the formula ##STR326## wherein each symbol is as defined in claim 1, or a pharmaceutically acceptable salt thereof.
 6. The method for treating osteoporosis according to claim 1, comprising administering a compound of the formula (I) wherein is --(NR³⁶)-- wherein R³⁶ forms a bond with R³⁵, R is alkyl, aryl, aralkyl or a group of a formula selected from the group consisting of:

    --(CH.sub.2)bN(R.sup.8)(R.sup.9)                           (1) ##STR327##

    --(CH.sub.2)bN(R.sup.10)CORa.sup.11                        ( 4)

    --(CH.sub.2)bN(R.sup.10)SO.sub.2 R.sup.44                  ( 5)

    --(CH.sub.2)bN(R.sup.10)COOR.sup.45                        ( 6) ##STR328##

    --(CH.sub.2)bCON(R.sup.47)(R.sup.48)                       (9)

    --(CH.sub.2)bOSO.sub.2 R.sup.44                            ( 10)

    --(CH.sub.2)bCOR.sup.49                                    ( 11)

and

    --(CH.sub.2)aCOOR.sup.1                                    ( 20)

wherein each symbol is as defined in claim 1 and the ring Q is a group of the formula ##STR329## wherein each symbol is as defined in claim 1, or a pharmaceutically acceptable salt thereof.
 7. The method for treating osteoporosis according to claim 1, comprising administering a compound of the formula (I) which selected from the group consisting of:9-tert-butyl-4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine, 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic morpholide, 4-(2-chlorophenyl)-6,9-dimethyl-2-(3-morpholinopropyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6-propyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 4-(2-chlorophenyl)-6-isobutyl-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6-phenyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 6-benzyl-4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-indolecarboxamide, N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-3-indoleacetamide, 6-benzoylamino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 4-(2-chlorophenyl)-2-ethyl-9-methyl-6-(3-(3-tolyl)ureido)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 8S-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine, 6-(2-chlorophenyl)-8,9-dihydro1,4-dimethyl-8-morpholino-carbonyl-4H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine, (4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid, N-(2-methoxyphenyl)-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide, N-phenyl-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide, N-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-p-toluenesulfonamide, (4-(4-methoxyphenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-methylphenyl)carbamate, 4-(2-chlorophenyl)-2-ethyl-9-methyl-6-phenylacetylamino-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, N-(4-chlorophenyl)-N'-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)urea, N-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methoxyphenyl)urea, N-(4-(4-chlorophenyl)-2-hexyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea, N-(4-(2-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea, N-(4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methoxyphenyl)urea, N-(2-ethyl-9-methyl-4-(4-methylphenyl)-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea, N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-phenylurea, N-(2-ethyl-9-methyl-4-phenyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea, N-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(2-methoxyphenyl)urea, N-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f]-1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-phenylthiourea, N-(2-butyl-4-(4-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(3-methylphenyl)urea, N-(4-(2-chlorophenyl)-2-ethyl-9-cyclohexyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N'-(2-methylphenyl)urea, 4-(4-chlorophenyl)-2-ethyl-9-methyl-6-(3-phenylpropyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,or a pharmaceutically acceptable salt thereof. 